systems biology: a vision for engineering and medicine

February 2007

Academy of Medical Sciences

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Systems Biology: a vision for engineering and medicine

A report from the Academy of Medical Sciencesand The Royal Academy of Engineering

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The Academy of Medical SciencesThe Academy of Medical Sciences promotes advances in medical science and campaigns to

ensure these are converted as quickly as possible into healthcare benefits for society. Our Fellows

are the UK’s leading medical scientists from hospitals and general practice, academia, industry

and the public service.

The Academy seeks to play a pivotal role in determining the future of medical science in the UK,

and the benefits that society will enjoy in years to come. We champion the UK’s strengths in

medical science, including the unique opportunities for research afforded by the NHS, encourage

the implementation of new ideas and solutions – often through novel partnerships, promote

careers and capacity building and help to remove barriers to progress.

The Royal Academy of EngineeringAs Britain’s national academy for engineering, The Royal Academy of Engineering brings together

the country’s most eminent engineers from all disciplines to promote excellence in the science,

art and practice of engineering. Our strategic priorities are to enhance the UK’s engineering

capabilities, to celebrate excellence and inspire the next generation, and to lead debate by

guiding informed thinking and influencing public policy.

The Academy’s work programmes are driven by three strategic priorities: enhancing national

capabilities; recognising excellence and inspiring the next generation and leading debate, each of

which provides a key contribution to a strong and vibrant engineering sector and to the health

and wealth of society.

ISBN No. 1-904401-13-5

1



February 2007

Acknowledgements

The Academy of Medical Sciences and The

Royal Academy of Engineering are most

grateful to Sir Colin Dollery FMedSci, Professor

Richard Kitney OBE FREng and the members of

the working group for undertaking this study.

The Academies thank the review group, the

Academies’ Officers, Council and staff and all

respondents to the consultation for their

informative comments and support. The two

Academies are grateful to the BBSRC for its

support.

Disclaimer

This report is published by the Academy of

Medical Sciences and The Royal Academy of

Engineering and has been endorsed by their

Officers and Council. Contributions by the

working group and respondents to the call for

evidence are made purely in an advisory

capacity. The review group added a further

‘peer-review’ stage of quality control to the

process of report production. The members of

the working group, the review group and the

consultation respondents participated in this

report in an individual capacity and not as

representatives of, or on behalf of, their

affiliated hospitals, universities, organisations

or associations (where indicated in the

appendices). Their participation should not be

taken as endorsement by these bodies.

© The Academy of Medical Sciences and


2

Contents

Foreword 4Summary 5Recommendations 7

1 Introduction 91.1 Background 91.2 Defining Systems Biology 91.3 The promise of Systems Biology 101.4 Scope of the report 11

2 Background 132.1 The challenge of biological complexity 132.2 The application of engineering principles to biological research 132.3 Trends and drivers 152.4 Approaches to building a system 182.5 Success stories 19

3 Opportunities 213.1 Introduction 213.2 The UK pharmaceutical sector 213.3 Drug research and development 213.4 Drug safety 243.5 Animal testing 253.6 Personalised healthcare 253.7 Complex diseases and scientific problems 273.8 Prevention versus treatment 293.9 Synthetic Biology 29

4 The current state of Systems Biology in the UK 334.1 Introduction 334.2 Centres 334.3 Capacity building 354.4 Other funding 364.5 Industry 374.6 DTI Beacon Projects 374.7 Medical Royal Colleges and Scientific Societies 384.8 The international picture 38

5 Imperatives 415.1 Working across cultures 415.2 Infrastructure: centres or distributed networks? 425.3 New systems biology centres of excellence in the UK 435.4 Additional investment 445.5 Leadership 455.6 Assessment and career progression 455.7 Education and training 475.8 The foundations of systems biology training 495.9 Education and training model 49

6 A 25 year vision for Systems Biology 51

Bibliography 53

Appendix I Working group and review group members 56

Appendix II Acronyms and abbreviations 58

Appendix III Consultation and call for evidence 59

3

CONTENTS

4

SYSTEMS BIOLOGY: A VISION FOR ENGINEERING AND MEDICINE

Foreword

Understanding the function of complex biological

systems is one of the greatest challenges facing

science. The rewards of success will range from

better medicines to new engineering materials. The

sequencing of the human genome, although of

fundamental importance, does not even provide a

complete parts list of the protein molecules that exist

in a biological organism because of complexities of

downstream processing and complex folding required

to make a functioning receptor or enzyme from a

long chain of amino acids. Furthermore, protein molecules do not function alone but exist in complex

assemblies and pathways that form the building blocks of organelles, cells, organs and organisms,

including man. The functioning of brain or muscle, liver or kidney, let alone a whole man, is much

greater than the sum of its parts.

To tackle this problem requires an iterative application of biomedical knowledge and experiment with

mathematical, computational and engineering techniques to build and test complex mathematical

models. Systems and control engineering concepts, a modular approach and vastly increased

computing capacity are of critical importance. The models, once developed and validated, can be

used to study a vastly greater range of situations and interventions than would be possible by

applying classical reductionist experimental methods that usually involve changes in a small number

of variables. This new approach is now termed "Systems Biology".

In addition to the impact that Systems Biology is likely to have in biomedical sciences, significant

potential exists in relation to its wider application in engineering and the physical sciences both

directly and via the associated field of Synthetic Biology. Such is the importance of Systems Biology to

the economy and to the future of both biomedical science and engineering that the Academy of

Medical Sciences and The Royal Academy of Engineering established a working party under our joint

chairmanship to enquire into the present situation in the United Kingdom and to make

recommendations for the future. The working party noted with approval the groundwork of the BBSRC

and EPSRC in the application of Systems Biology to molecules and cells and identified great

opportunities for developing Systems Biology applications to whole organs, complete organisms and

particularly to man. The report outlines those opportunities, recommends substantially increased

investment and considers the financial, organisational, manpower and educational developments that

will be needed. It is primarily aimed at policy and decision makers in a range of fields. This

constituency comprises government, industry, Research Councils, other grant giving bodies (eg.

Wellcome Trust), the Fellowships of the two Academies, the medical Royal Colleges and universities. It

is also anticipated that the report will be of considerable interest to international bodies such as the

European Commission and the World Health Organisation.

In an world increasingly dependent upon R&D and knowledge, Systems Biology is an area in which

the United Kingdom must compete if it is to secure economic progress.

Sir Colin Dollery Professor Richard Kitney

Sir Colin Dollery Professor Richard Kitney

5

SUMMARY

Systems Biology is a groundbreaking scientific

approach that seeks to understand how all the

individual components of a biological system

interact in time and space to determine the

functioning of the system. It allows insight into

the large amount of data from molecular biology

and genomic research, integrated with an

understanding of physiology, to model the

complex function of cells, organs and whole

organisms, bringing with it the potential to

improve our knowledge of health and disease.

Systems Biology has become a viable approach

as a result of recent developments in the

biological sciences, systems engineering,

imaging, mathematics and computing. It uses

an iterative cycle of computational modelling

and laboratory experiment to understand how

the components work together in a system, a

characteristic feature of Systems Biology. This

method offers a wealth of opportunities across

medicine, engineering and other fields. One of

its most immediate impacts will be in the

pharmaceutical sector where, by means of a

more effective drug development process,

Systems Biology will bring innovative drugs to

patients more quickly and cheaply. It will be a

vital tool in elucidating the many interacting

factors that contribute to the causes of

common medical conditions, in the near-term

yielding important information on

cardiovascular disease and liver function and,

in the longer term, increasing our

understanding of cancer and dementia.

Systems Biology will provide a platform for the

development of Synthetic Biology: the design

and re-design of biological parts, devices and

systems with applications ranging from

materials with enhanced properties to biofuels.

The US currently leads the world in many

aspects of systems biology research. Growth is

also rapid in Japan and several other EU

countries. Against this background, UK systems

biology research is patchy. The recent and

welcome Biotechnology and Biological Sciences

Research Council (BBSRC)/Engineering and

Physical Sciences Research Council (EPSRC)

investment in Systems Biology of molecules and

cells has not been matched by a corresponding

investment in organ systems and whole

organisms. Growth in Systems Biology is

threatened by the serious decline in UK capacity

in its underpinning disciplines, including many of

the physiological, pharmacological, engineering,

mathematical and physical sciences. The

interdisciplinary nature of Systems Biology also

presents a challenge to the traditional structure

of UK academic research and training, as well as

to current arrangements for research funding

and assessment. Interdisciplinarity is an

increasingly important feature of most scientific

research, but there is an urgent need to

catalyse activity at these new interfaces and so

avoid important aspects of this work falling into

gaps between university departments and

research funders.

Recent initiatives by the BBSRC and the EPSRC

have undoubtedly energised UK systems

biology research at the level of cells and

proteins. Nevertheless, there are vast

unexploited opportunities at the levels of

tissues, organs and whole organisms,

particularly in medicine and the

pharmaceutical/biotechnology industries, as

well as in the emerging field of Synthetic

Biology. Failure to build the systems and

synthetic biology research base will have

important consequences for UK science and

ultimately for public health and economic

prosperity. Without sufficient UK capability, top

researchers will be attracted abroad. Industry

could also look to the US, South Asia and the

Far East for research and development

opportunities.

Summary

6


The potential of Systems Biology will only be

realised if the UK Government takes

determined and prompt action. There is a

pressing need for a major and sustained

initiative to build capacity in terms of human

capital, research infrastructure and additional

resources. Future generations of systems

biologists will require formal training in

biological, engineering and mathematical

sciences, with undergraduates exposed to

interdisciplinary problems while being trained

in a core discipline. New and extended

postgraduate courses in Systems Biology

should be created, along with an expansion in

postdoctoral opportunities. New centres of

excellence should be established to build

capacity and pursue research in areas that are

not being explored by existing or planned

initiatives. In bidding for these new centres,

universities should specify their plans to

address the structural, organisational and

human resource issues known to hinder

interdisciplinary research.

Ensuring that the UK secures an internationally

competitive position in Systems Biology

requires substantial new investment by

government and industry, together with a

change in attitudes and working practices in

the universities. Central to success will be the

coordination of activities across academia,

industry, research funders, the NHS and

government. Systems Biology will inevitably

become an approach that pervades scientific

research, in much the same way that molecular

biology has come to underpin the biological

sciences. It will transform the vast quantities of

biological information currently available into

applications for engineering and medicine. The

recommendations in this report represent

essential steps towards the realisation of this

potential.

7

Recommendations

Systems Biology: its role in advancing knowledge and building the nation’s wealth

Systems Biology, the iterative application of mathematical modelling and engineering systems

analysis to biological and medical systems, promises to transform our understanding of

physiology and medicine and yield wide-ranging applications in engineering, biotechnology,

pharmaceutical development, clinical medicine and public health. It is of critical importance in

building the nation’s wealth. Such is its relevance that the two Academies recommend a major

additional investment, in addition to that already being made by the BBSRC and the EPSRC.

1. Establish a number of new major systems biology centres in the UK

The new centres should be located within leading universities that have internationally

competitive research in biology, medicine, engineering and physical sciences. They must be a

focus of activity effectively networked to smaller centres in other universities, including those

currently being established by the BBSRC and the EPSRC, and linked to international

initiatives. It is essential that centres seek collaborations with industry and the NHS to ensure

that projects of high national economic importance receive priority. Systems Biology is

destined to become a pervasive scientific approach and advancing this objective should form

part of the mission statement of the centres. Centres must be outward looking and avoid

becoming scientific ghettos. Their remit should focus on world-class research, ranging from

basic science to clinical practice and industrial products, and should include formal training

and education (i.e. Masters and PhD programmes) in Systems Biology (including Synthetic

Biology, which involves the design and re-design of biological parts, devices and systems -

with applications ranging from materials with enhanced properties to biofuels). The

programme for each individual centre should reflect the strengths of the university (or

universities) taking part, but each centre will need to have a mixture of biology and medicine

on the one hand and engineering, physical sciences and mathematics on the other.

Funding should be allocated on the basis of competitive bids to Research Councils UK and

centres should be chosen to tackle a wide range of challenging research topics. Examples of

topics that might form part of the work of centres include: the toxicity and safety of

medicines; the function of neuronal synapses; the growth of human cancers; ageing; and the

spread of infections in hospitals. However, this list is neither comprehensive nor exhaustive

and is not intended to limit applicants. The example of the BBSRC and the EPSRC might be

followed with a first phase succeeded by one or more additional phases. Engineering

research, particularly in the field of Synthetic Biology, is set to grow rapidly and must form a

significant part of the work of some of the centres proposed in this initiative.

2. Additional investment

An investment of approximately £325m is required over a period of 10 years to establish

three to five new centres. This consists of approximately £75m for initial capital costs to be

spent over the first three years, and £24m per annum as recurrent expenditure. The size of

each centre may vary. It is estimated that, at current prices, a centre capable of housing

between 30 and 35 scientists and support staff, as well as up to 30 doctoral students, would

have a core recurrent budget of £5m a year, including consumables. Additional costs would

be incurred for equipment, constructing new buildings or adapting existing facilities. A capital

budget of about £15m per centre would be necessary to meet this expenditure, although, as

far as possible, existing resources should be re-deployed by the host university. Centres of

RECOMMENDATIONS

8


this size would provide sufficient capacity to work on one major project and one or two

subsidiary projects. After 10 years, successful centres should be progressively integrated into

their host university.

The new initiative would be more costly than the present BBSRC/EPSRC programme because

of the inclusion of projects involving a substantial engineering and medical component.

Hence, additional government support is needed to realise this important opportunity for the

UK. Partnerships should also be sought to offset part of these costs through strategic

collaborations with industry, medical charities, the MRC, NHS R&D and the DTI.

3. Interdisciplinary research environment

Universities bidding for one of the new centres should be required to specify their plans for

addressing the structural, organisational and human resource issues that are known to hinder

interdisciplinary research. Implementation of these plans would be a condition of a successful

grant application.

The interdisciplinarity of Systems Biology poses a challenge to the traditional structure of

university departments and the current arrangements of research grants committees in the

public, private and charity sectors. Academic organisation, funding streams and research

assessment mechanisms must evolve to encourage growth of interdisciplinary research

activities such as Systems Biology. This needs to be reflected in approaches to leadership,

career development, peer review and publication criteria. Universities must break down

barriers between disciplines and consider new methods of organisation that promote the

development of novel scientific approaches. A substantial change in culture is required, in

which biology and medicine become more quantitative. The Research Assessment Exercise,

as currently structured, continues to be a barrier to interdisciplinary research.

4. Interdisciplinary skills

Given the urgent need to develop the skills required to undertake Systems Biology, new

postgraduate courses and the expansion of postdoctoral opportunities should be created. For

instance, undergraduates, including medical students, should be offered options in the core

disciplines that support Systems Biology, as well as increased exposure to interdisciplinary

problems and modules.

Further urgent action is needed to revive subjects important to the development of Systems

Biology such as physiology, pharmacology, engineering and mathematics. Such initiatives in

education and training should be closely coordinated with programmes in the BBSRC/EPSRC

centres.

Systems Biology is not simply an exercise in mathematical modelling: it requires a deep

knowledge of the complexities of the biomedical problem being addressed, together with a

thorough understanding of the power and limitations of the engineering and mathematical

concepts being used. Courses in biology and medicine for engineers, mathematicians and

physical scientists are crucial, but they must be combined with an expansion of mathematical

training for biological and medical scientists to develop multi-skilled, interdisciplinary teams.

Initially, in view of the shortage of trained personnel in the UK, there may be a need to

create schemes that establish a new cadre of young systems biologists, involving overseas

recruitment where necessary.

9

1 INTRODUCTION

1.1 Background

Groundbreaking developments in the biological

sciences over the past 50 years have

dramatically improved our understanding of

human health and disease, an important

example being the publication of the initial

sequence of the human genome. This

remarkable progress in biology has been

accompanied by equally important

developments in imaging technologies, systems

engineering, signal processing, mathematical

biology, computation and in our ability to model,

design and realise ever more complex systems.

The genetic code (specifying the proteins that

form the main building blocks of all life) has

been likened to a parts list for an engineering

project. The reality is, however, that only very

limited information about function can be

deduced directly from the genome. Knowledge

derived from the genome has already had an

enormous impact on biology and medicine but,

whereas the individual function of some

proteins may be well known, the interactions

between the many proteins that constitute a

system and how they function together are

poorly understood. This is attributable to a

distinctive feature of biological systems, that of

‘emergent behaviour’, whereby the whole is

more than the sum of its parts.

Scientists are now facing the challenge of

turning the vast quantities of descriptive

information from the revolution in molecular

biology into useful knowledge that can aid the

understanding of the overall function and

behaviour of systems. Hence, we are now

entering a new era of biology and medicine

where the mechanisms that underpin health

and disease at the levels of genes, proteins,

cells, organs, physiological systems and whole

organisms are being progressively uncovered.

The complexity and interrelationships of these

systems challenge standard ways of scientific

description and understanding and require a

new paradigm – Systems Biology – an

approach underpinned by the life, physical and

engineering sciences.

Systems Biology assimilates the advances in

these fields to create an innovative and

powerful scientific approach. It will become

pervasive and influential throughout biology,

medicine and engineering, in a manner similar

to the way in which molecular biology

underpins much of biomedicine today.

1.2 Defining Systems Biology

Systems Biology is an emerging methodology

that has yet to be defined. Nevertheless, what

most people would describe as ‘Systems

Biology’ is being applied in many different

contexts. A MedLine search for ‘Systems

Biology’ in 2000 revealed fewer than 10

papers1. In early 2006, a similar search

produced nearly 700 papers. Rather than

providing a rigid definition that might quickly

be overtaken by scientific advances, this report

offers instead a working definition so that its

future impact and opportunities can be

considered.

For the purposes of this report, Systems

Biology is defined as the quantitative analysis

of the dynamic interactions between several

components of a biological system and aims to

1 Levesque & Benfey, 2004

1. Introduction

‘…we need to overcome the idea, so prevalent in both academic and bureaucraticcircles, that the only work worth taking seriously is highly detailed research in aspeciality. We need to celebrate the equally vital contribution of those who dareto take what I call "a crude look at the whole".’

Murray Gell-Mann, Nobel Laureate in Physics, 1994

10


understand the behaviour of the system as a

whole, as opposed to the behaviour of its

individual constituents. It applies the concepts

of systems engineering to the study of complex

biological systems through iteration between

computational and/or mathematical modelling

and experimentation.

Thus, unlike much of traditional reductionist

biomedical sciences, Systems Biology

investigates the functioning of a biological

system as a whole, rather than studying

individual components in isolation. It is

underpinned by many disciplines including

engineering, medicine, biology, physiology,

pharmacology and chemistry, computing,

mathematics and physics. In addition, it draws

upon and often contributes to bioinformatics,

mathematical biology and the ‘omic’ sciences.

1.3 The promise of Systems Biology

Systems Biology will affect many areas of the

biomedical sciences, healthcare and

engineering. The recent Government strategy

on ‘Best Research for Best Health’ emphasises

the importance of translating world-class

research into clinical practice, to which

Systems Biology can contribute considerably2.

In the near future, positive outcomes are likely

to be first observed in the pharmaceutical

sector where Systems Biology can advance the

research and development of new and specific

drug targets, thus contributing to the move

towards personalised medicine.

Systems Biology bridges the gap between

biology and engineering, utilising fundamental

principles such as systems analysis, control

and signal theory from the latter. In return,

Systems Biology provides the foundation for

the development of Synthetic Biology: the

design and construction of new biological parts,

devices and systems, and the re-design of

existing, natural biological systems for useful

purposes3. In the long-term, advances in this

field will provide innovative engineering

solutions (e.g. stronger and lighter materials)

that have the potential to drive wealth creation

in several industry sectors.

The UK Government’s Science and Innovation

Investment Framework 2004-2014 identifies

Systems Biology as an exemplar of

multidisciplinary research and an area where

the UK has current world-class strength and

could develop a lead. Although figures

demonstrating the benefits of Systems Biology

are not given, the following are identified as

some of the key outcomes4:

• A skills base that is fit for the future - a

critical mass of highly skilled researchers

able to function to a high standard in a

multidisciplinary research environment.

• More effective therapeutics that tackle the

underlying causes of disease rather than

treating the symptoms - pharmaceuticals

with fewer side effects.

• Providing bio-industry with the ability to

model and manipulate biological processes

better so as to provide novel compounds for

the chemical, pharmaceutical and food

sectors, thereby improving the competitive

edge of these industries.

• A better understanding of healthy ageing

and how to maintain a population that

remains healthy and productive for longer.

• The development of predictive (in silico)

toxicology models of cells and organs leading

to improved drug screens and reduced need

for animal testing.

Clearly, Systems Biology is of national

importance and transcends the work of several

Research Councils. Given the health and

economic opportunities that it presents, as well

as the substantial international and industrial

interest, a major national initiative is needed to

build upon the current efforts of the BBSRC,

the EPSRC and others.

2 Department of Health, 2006

3 http://syntheticbiology.org

4 HM Treasury, 2004

11

1 INTRODUCTION

1.4 Scope of the report

In 2005, the Academy of Medical Sciences and

The Royal Academy of Engineering identified

Systems Biology as an area of scientific and

economic priority and established a joint

working group to undertake a review of

developments and opportunities in the UK.

Members and reviewers are identified in

Appendix I.

The working group adopted the following terms

of reference:

• To provide a high-quality review of the

existing activity and capacity within the UK,

highlighting positive and negative

differences in Systems Biology research

capability through comparison with other

countries.

• To consider the role of biomedical science

and engineering in the context of Systems

Biology and how the interface between the

two disciplines, and others, should be

developed to maximise opportunities.

• To consider potential developments in

Systems Biology and their likely impact.

• To identify key policy issues relating to

Systems Biology and its potential

contributions to the health and wealth of

the nation.

• To produce an authoritative report,

accessible to both the specialist and lay

reader.

• To advise government, industry, academia

and other stakeholders of the findings of

the report and, where appropriate,

recommend action.

• To determine the characteristics that

Systems Biology research exhibits for

providing a working definition of the term.

Systems Biology is likely to have a significant

impact on many areas of science and

technology including plant science, food

microbiology, energy and environmental

science. Although the importance of these and

other topics was acknowledged, the two

Academies decided upon a sharper focus that

was closely aligned with the interests of their

constituencies. It was agreed that the project

should focus on the biomedical and

engineering applications of Systems Biology.

The report therefore addresses research

ranging from macromolecules to the whole

organism in both academia and industry. It also

addresses issues of education in this novel and

evolving field.

In 2005 the two Academies issued a series of

calls for evidence to UK universities, research

funders, medical research charities, Scientific

Societies, medical Royal Colleges, government,

industry and others. The information gathered

was considered and assimilated in the

production of this report, along with the

evidence that emerged from meetings with key

stakeholders and extensive published material.

Names of respondents to the consultation are

given in Appendix III.

This report has been prepared to inform policy-

makers, government, research funders,

universities, academics and industry, as well as

other interested parties.

The five chapters that follow expand upon this

introductory section and examine respectively:

• The scientific and technological

developments that are now making a

systems approach viable.

• The potential and opportunities of Systems

Biology for groundbreaking progress in

biology, medicine and engineering.

• The evidence gathered over the course of

the inquiry.

• The issues that must be addressed without

delay to enable Systems Biology to develop

to a degree that makes the UK a leading

country in its development and exploitation.

• The advances that are likely to characterise

the field in the next 25 years.

12


What is Systems Biology? How does it differ fromconventional Biology?

The science and the technology underpinning Systems Biology.

The potential of Systems Biology to improve the healthand increase the wealth of the nation. The prospects forbiology, medicine and engineering.

Ongoing research activities in the country andcomparison with developments abroad.

Imperative prerequisites for the growth of SystemsBiology in the UK.

Systems Biology in the future: what developments arelikely to take place in the next 25 years?

Introduction

Background

Opportunities

Current state of SystemsBiology in the UK

Imperatives

A 25 year vision for SystemsBiology

13

2 BACKGROUND

2.1 The challenge of biologicalcomplexity

Biological systems exhibit complexity at

multiple spatial levels. The human genome may

only have about 25,000 genes, but these are

used to make over 100,000 proteins, many of

which serve more than one function. The

number of conceivable interactions between all

the human genes and their protein products is

so immense (around 2e166713) that evolution can

have explored only a minute fraction of these

interactions during the four billion years of life

on Earth5. Even if we consider only pairwise

interactions between the proteins, five

thousand million combinations are possible.

However, some interactions are more likely than

others because evolution is a very efficient

process: it does not try out combinations

randomly, but operates along pre-existing sets

of connections.

Tissues and organs are the next level of

biological complexity. Even apparently

homogeneous organs, such as the liver,

function in a systematic coordinated manner

far different from the isolated behaviour of the

cells that constitute them. Cells are also

acutely sensitive to the surrounding

environment and their interactions with

adjacent cells: for instance, isolated liver cells

in a nutrient solution may remain alive but

quickly lose many of their specialised functions.

More complex still is the whole organism that is,

again, much more than the sum of its organ and

cellular parts. Although not the main focus of

this report, a further level of biological

complexity comes at the level of populations of

organisms, where topics as diverse as the

spread of infectious disease, ecosystems and

economies have been researched.

Biological complexity cuts across time as well

as space. At the molecular level timescales of

10-9 seconds, characteristic of Brownian

motion, are important, whereas at the level of

the whole organism the systems might be

considered over 109 seconds, of the order of a

human lifetime6. Figure 1 illustrates the wide

range of spatial and temporal levels that need

to be taken into account when trying to

understand biological systems. Systems

Biology can help to unravel this biological

complexity, and provide knowledge of the

function of biological systems.

2.2 The application of engineeringprinciples to biological research

2.2.1 Systems theory

The publication of Norbert Wiener’s book,

‘Cybernetics’, established the basis for studying

systems within the human body using systems

theory7. Signal processing is another very

important area of engineering that, together

with systems theory, has applications in a wide

range of fields, including physiology. Within

Systems Biology, systems theory and signal

processing can be used to understand how the

body works at different spatial and temporal

levels.

Systems theory has been used in the design,

construction and study of aircraft control

systems, information and telecommunication

networks and economies. Control systems in

different organisms tend to have very similar

5 ‘There wouldn’t be enough material in the whole universe nature to have tried out all the possible interactions even over the long period of billions of years of the evolutionary process’. Noble, 2006.

6 Hunter et al., 2002

7 Wiener, 1948

2. Background

‘Considering the inconceivable complexity of processes even in a simple cell, it islittle short of a miracle that the simplest possible model - namely, a linear equationbetween two variables - actually applies in quite a general number of cases.’

Ludwig von Bertalanffy, biologist, 1968

14


8 Hunter et al., 2002. With kind permission of Springer Science and Business Media. © Springer-Verlag 2002.

building blocks and commonalties can be

exploited for scientific investigation. Key

elements of systems theory are the concepts of

feedforward and feedback loops and

modularity. A feedforward loop refers to that

part of a system where information flows in

order to produce some form of action. A simple

example is that of a driver turning the steering

wheel of a car thus leading the vehicle to follow

a bend in the road. Here, both the driver and

the steering mechanism are part of the overall

system for steering the car. In contrast, a

feedback loop refers to that part of a system

that is used to monitor a situation: here

information is fed back to a central point that

monitors the performance of the system. In

the context of the previous example, this

would involve the driver looking at the bend in

the road and the visual information being fed

back to the visual cortices in the brain. The

system then compares the position of the car

in relation to the bend and, if necessary,

prompts further action.

2.2.2 Modularity

Modularity refers to the ability within systems

theory and engineering design to consider

systems as a set of constituent parts. In the

example given above, the components of the

feedforward loop consist of the driver’s brain

and the musculoskeletal system (one module)

and the steering mechanism of the car (the

second module). In the feedback loop the

modules comprise the driver's eyes and his

brain. In both engineering and biology,

systems often include multiple feedforward and

feedback loops with multiple modules, as well

as loops that operate at different spatial and

temporal scales. However, such systems often

consist of a set of standard modules which,

when put together, produce a particular

emergent function.

Modularity is a key principle of the analysis of

engineering systems. One of the fundamental

questions for system biologists is whether

modularity is a universal principle in nature or

just a property of certain classes of biological

systems. The realisation that gene duplication

and subsequent modification by mutation and

natural selection is a fundamental process in the

evolution of organisms gives strong support to a

modular approach. In fact, life forms constantly

re-use systems that already exist rather than

taking time to evolve new gene products.

2.2.3 Systems analysis

Systems analysis is not simply computational.

In many ways it is reminiscent of physics in

that it seeks ‘laws’ or general principles of

Figure 1: Spatial and temporal levels encompassed by biological systems8.

10-6s 10-3s 100s 103s 106s 109smolecular events diffusion motility mitosis protein human

(ion channel gating) cell signalling turnover lifetime

Gene Pathway models Stochastic models Ordinary Continuum models Systems modelsNetworks Differential (Partial Differential

Equations Equations)

Atom Protein Cell Tissue Organ Organ system10-12m 10-9m 10-6m 10-3m 100m & organism

Protein Cell Tissue Anatomy Physiology

15

2 BACKGROUND

systems operations exemplified by the laws of

metabolic and hierarchical control analysis. It is

also mathematical, in that it questions the logic

of the system, including the constraints it

operates under, the degree of modularity of

functions in organisms, their robustness (fail-

safe mechanisms) and the rules for

development. Ultimately it must align with

quantitative theories of evolution. These are

vast wide-ranging questions and there is

considerable disagreement on the extent to

which such logic of systems operates,

compared with the serendipitous process of

historical evolution.

2.2.4 Biological systems

Biological organisms are much more

complicated than any machine designed by

man. However, there are similarities between

the way in which organs and whole organisms

are assembled from molecules and cells and

the design methods used by engineers in the

construction of complex systems. The

application of such methods to biology will,

however, require novel engineering tools to be

developed since biological systems possess key

features that artificial ones do not. Specifically,

biological systems have an exceptional capacity

for self-organisation and assembly, using rules

and mechanisms that have been shaped by

natural selection. Biological systems also have

significant capacity for continuing self-

maintenance through turnover and renewal of

component parts. Perhaps the property that

distinguishes biological systems most is their

ability to auto-adapt their organisation to

changing circumstances through altered gene

expression, or more directly, through signal

transduction and modification of proteins. This

adaptation culminates at higher levels of

organisation as evidenced by phenomena such

as the development of resistance to antibiotic

therapy or tolerance to recreational drugs.

The mechanisms by which component parts

interact are often highly stochastic in nature;

that is, susceptible to the play of chance, which

becomes particularly important when only a

few components are being considered.

Nevertheless, biological systems are robust.

2.3 Trends and drivers

The application of a systems biology approach

to a biomedical question depends upon the

quality and quantity of the data available about

the system under study. Systems thinking is

not new to biology, having been historically

applied in the physiological sciences and

elsewhere. However, it had to be abandoned

because of the lack of necessary data and

tools9. To date, persisting difficulties in

informing models with sufficient and adequate

experimental data are driving a convergence of

several disciplines as diverse as molecular

biology, computing and mathematics to enable

the progress of Systems Biology. Key drivers

are outlined below. The list that is far from

comprehensive as other authors have already

provided more detailed discussion about the

roots of Systems Biology10, 11

.

2.3.1 Molecular biology

The revolution in molecular biology, manifest in

the Human Genome Project, has driven and

has been driven by technological advances that

have simplified the simultaneous measurement

of a large number of biological parameters.

Examples include microchip arrays that employ

antibody fragments for detection and

measurement of thousands of gene products

(mRNA) in a single assay and the development

of similar chips for use with protein molecules.

More established techniques, such as mass

spectrometry, have made comparable progress

and are now capable of measuring molecules of

higher mass with greater throughput. These

advances are helping the provision of ever

more quantitative information about biological

systems at different spatial and temporal levels

and can be employed to make more useful and

predictive models.

9 Westerhoff & Palsson, 2004

10 Westerhoff & Palsson, 2004

11 World Technology Evaluation Centre, 2005

16


2.3.2 Bioinformatics

Advanced informatics and bioinformatics play a

major role in the handling and interpretation of

the vast amount of data generated by the

developments characterising molecular biology

in the last 50 years. About 50 terabytes of

descriptive data relating to the human genome

have already been acquired but its use rests

upon its conversion into operational

information, which remains a fundamental

challenge. Success in this enterprise will be

critically dependent on the ability to extract

data from the many sources (databases and

literature) and bring it together in a mutually

intelligible format that describes the structure

and function of complex biological systems.

2.3.3 Imaging

Biological systems operate in four dimensions

and their spatial and temporal organisations

are critical to function. Advances in imaging

methods have been, and will be, critical to

biology and medicine, and to Systems Biology.

For instance, imaging is increasingly being

used to understand the action of

pharmaceuticals in vivo and will deliver the

direct application of systems approaches to

clinical medicine. Significant parallels exist

between advanced imaging and Systems

Biology in that both require a combination of

mathematical, statistical and biological

training. Neuroscience, for instance, is an area

where close relations between biologists and

imaging scientists will be essential and where

Systems Biology will play a significant role in

translational/experimental medicine.

It is essential that imaging scientists and

systems biologists develop and maintain a

dialogue. Imaging is progressing rapidly and

opportunities exist to influence some of its

developments for the provision of appropriate

tools for Systems Biology. Currently, the

gathering of adequate data for the

development of models that test the behaviour

of biological systems over time is extremely

difficult. A key tool will be high resolution and

dynamic functional imaging, from which, for

example, dynamic time series data can be

automatically extracted at a single cell level in

living cells.

2.3.4 Computer power and information and

communication technologies

Since 1994 the power of computers has

continued to expand rapidly. As Gordon Moore

predicted in 1965, the number of transistors on

a silicon chip has doubled every 18 months and

looks set to continue to do so12

. Increased

computing power supports Systems Biology by

helping researchers to build and use ever more

complex models.

As systems biology data mining becomes

increasingly intensive, the computational

power that will be required for more

sophisticated applications in the future is likely

to exceed the capabilities of local computers.

Furthermore, the demand for computational

operations involving data sources that may be

distributed across many sites, where they are

maintained and updated on a regular basis, is

increasing along with the interactions between

researchers working in different and often

distant locations. In circumstances such as

these, telecommunications and distributed

computing are key to the exchange of

information. For reasons relating to cost and

because they are already in place, commercial

telecommunication systems, ranging from

relatively slow standard telephone lines to

much faster ATM networks, are often used. For

instance, downloading a set of 10,000 images

from a distributed database via a standard (i.e.

domestic) broadband connection would take

2.7 minutes per image and therefore a total of

18 days. However, much faster networks are

available for academic purposes. For example,

the California Research and Education Network

(CALREN) allows the downloading of images at

a rate of 80ms each; it therefore takes only 10

minutes to download the whole set. Hence,

major infrastructures such as distributed

processing, federated databases and grid

computing are likely to be required for the

progress of Systems Biology. In the area of

12 Moore, 1965

17

2 BACKGROUND

distributed computing significant progress has

been made already by the UK e-science

initiative, supported by the relevant Research

Councils and embodied in the national and

regional e-science centres. This has placed UK

e-science in a strong international position and

illustrates the importance of maintaining and

expanding the infrastructure for the support of

future systems biology developments.

2.3.5 Modelling

The meaning of the word ‘model’ is highly

dependent on the context of use. Within this

report the term ‘modelling’ refers to predictive

modelling of the underlying process that

generates the experimental data, rather than

modelling the data itself. Modelling is already

well developed within engineering,

mathematics and physics and is beginning to

be more widely used within the life sciences.

Mathematical and computational modelling of

living systems is a key feature of Systems

Biology and is used to make predictions about

complex biological structures and functions.

A model is a simplified and abstract

reproduction that allows insight into the

essence of a system and helps to identify gaps

in biological knowledge. It is instrumental in

the management of the complexity of biological

systems where all the variables that might be

of interest need to be monitored

simultaneously, and simulates and yields

results that approximate to the emergent

behaviour of the biological system under

scrutiny13

. Its output may indicate a limited

range of experiments whose results may, in

turn, be used to test and refine the model by a

cycle of iteration between simulation and

experimentation (Figure 2). Within Systems

Biology, modelling therefore complements

observation and experimentation, helping to

deepen our understanding of the dynamics

within the system being studied14

.

Biological systems encompass a wide range of

spatial and temporal scales, each of which

requires a particular kind of quantitative

analysis. However, substantial incompatibilities

still exist between the mathematical

formulations at each of these different scales,

and this constitutes one of the key challenges

that currently face systems biologists.

2.3.6 Statistical inference

Statistical inference plays an important role in

Systems Biology. Many systems involve large

numbers of components whose interactions are

each governed by rate factors that must be

estimated from experimental data. Moreover,

the networks underpinning such systems may

not be known in detail, in which case both the

structure of the network and its constituents

must be inferred. To make matters yet more

challenging, the constraints of biological

experimentation are often very different from

those that characterise engineering and the

physical sciences, requiring that engineers,

mathematicians, statisticians and biomedical

scientists interact closely to develop the most

effective solutions to entirely novel classes of

problems. Inference is at the cutting-edge of

statistical research and its further growth will

be a key component to progress in Systems

Biology.

13 Finkelstein et al., 2004

14 BBSRC, 2003

15 Kitano, 2002. Copyright 2002 AAAS. Readers may view, browse, and/or download material for temporary copying purposes only, provided theseuses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed,transmitted, modified, adapted, performed, displayed, or sold in whole or in part, without prior permission of the publisher.

Figure 2: Hypothesis driven research in Systems Biology15.

18


2.3.7 Engineering design

Advances in engineering design and techniques

carry a significant potential in driving the

progress of Systems Biology. Interventions to

biological systems intended to improve health,

whether environmental, pharmacological or

clinical, need to be carefully thought through

and carried out to maximise benefit and reduce

harm. The refinement of techniques and tools

enables devices and systems to achieve a

defined performance within precise tolerance

limits, potentially allowing better interventions

to complex biological systems. They will be

increasingly necessary to permit more reliable

system-wide predictions of the effects of

biomedical advances and to achieve desired

clinical results to a predefined tolerance, or at

least to have a quantitative bound on the

biological uncertainty.

2.4 Approaches to building a system

2.4.1 Molecular to cellular systems

A systems approach to molecular biology seeks

to enable the prediction of the functioning of a

cell given a sequenced genome and, ultimately,

the behaviour of networks of cells. At present,

this is not feasible and even predicting the

interactions of a functional group of proteins on a

signalling pathway is extremely challenging. The

progress of Systems Biology depends strongly on

the development of models of complex systems.

In turn, this requires sufficient and accurate

experimental data about the behaviour of the

system under study (top-down) and about the

structure and function of the component

molecules (bottom-up). In practice, a judicious

combination of the two, sometimes referred to as

the ‘middle-out’ approach, may be the most

practical solution. If this can be done,

experimental biology and medicine will gain vast

benefits from the simulation of complex systems

and development of models with predictive

capabilities. Examples of current research foci

include modelling sensory networks, initially of

bacteria, with the possibility that this may be

extended to multicellular organisms, including

plants and animals.

To date, efforts in the field of Systems Biology

have focused on the use of models to represent

the interaction between proteins. However, it is

not yet clear how to incorporate the structural

and biophysical properties of the constituent

molecules. Even simple cellular networks can

display highly complex behaviour if either long-

range connections or the spatial heterogeneity

of the in vivo intra-cellular environment, or

simply the nonlinearity of the kinetics, are

included as the system’s parameters. It is

therefore challenging to scale-up models to

higher levels. Arguably, stochastic models,

those that contain ‘random’ elements, may be

able to provide the bridge between molecular

level and higher-level descriptions. These

models have had some success in describing

the behaviour of small numbers of molecular

components evolving in time, but it is still not

clear how to set parameters that may have an

effect both on the molecular level and the

higher level descriptions.

2.4.2 Whole-organ modelling

An exhaustive bottom-up reconstruction of a

complex organ such as the heart would be very

difficult. Therefore, when modelling higher-

level physiological systems, activity at lower

spatial levels is represented with simplified

equations. The engineering principle of

modularity discussed earlier in this chapter can

be exploited so that sub-systems within a

larger model are represented by ‘black boxes’,

interconnected with feedback and feedforward

loops, where the input and output, but not the

intervening steps, are considered. Ultimately,

advances in Systems Biology will also allow the

detailed understanding of the function of these

black box modules. Such modularity permits

the adoption of a middle-out, rather than

bottom-up or top-down, approach. When

choosing the middle-out option, analysis starts

at the level for which there are large amounts

of usable data and then reaches out in either

direction (this is the ‘out’ part of the metaphor)

to consider the next linked modular sub-

system. All three approaches are needed,

although the general view is that top-down and

19

2 BACKGROUND

middle-out approaches are likely to be more

fruitful in addressing future therapeutic needs,

at least for the near-term future. Modularity also

enables the identification of relevant features of

the lower-level mechanisms. Importantly, this

allows the complexity of the overall model to be

kept within bounds; for example, sodium or

calcium transport can be described by a few

simple equations. It is important to note that

incomplete or approximate models can have

significant value and application, and it is not

necessary to wait for all the details of a system

to be defined before a model can be used.

Indeed, the outcome of a model can be used in

combination with experimental data for further

refinement of the model itself through the cycle

of iteration between modelling and

experimentation described earlier.

The results of modelling complex systems are

frequently counterintuitive. Beyond a certain

degree of complexity, qualitative thinking is not

only inadequate, it can even be misleading. A

good example of this is provided by the

mechanism of mechano-electric feedback, in

which the contraction of the heart influences its

electrical properties. Some of the results,

particularly on the actions of changes in cell

volume (characteristics of many disease

states), are unexpected and have been

responsible for determining the next stage in

experimental work. The unravelling of such

complex physiological processes can only occur

as a result of the iterative exchange between

experiment and simulation.

2.5 Success stories

Systems Biology is increasingly contributing to

the understanding of medical conditions and

the way these react to treatments. For

instance, the US company Entelos Inc. has

developed functional computer models of

diabetes, obesity, rheumatoid arthritis and

asthma that are being used in the design of

clinical trials16

.

As part of the Physiome Project, a model of the

heart has also been developed to assess the

risk of ‘torsade de pointes’ (a potentially fatal

cardiac arrhythmia that can be provoked by

rare inherited conditions affecting an ion

channel in the heart) and test some therapeutic

drugs that prolong the repolarisation of the

heart muscle by inhibiting the function of this

channel (see section on cardiac toxicity in

Chapter 3). The model has already been used

successfully in the assessment of drug safety

by regulatory bodies in the US and Europe.

Another successful model has been developed

to assess the determinants of the response to

COX inhibitors, an analgesic class of drugs.

There is a relatively poor correlation between

the blood plasma concentration of this class of

drug and the analgaesic or adverse effects in

chronic inflammatory conditions. Consequently,

it is difficult to predict the appropriate dose

regimes for the treatment of chronic

inflammatory pain. The modelling of changes in

endogenous mediators of inflammation has

helped to elucidate the relation between

exposure to the drug and the therapeutic

response17

.

16 www.entelos.com

17 Huntjens et al., 2005

20


21

3 OPPORTUNITIES

3.1 Introduction

As well as advancing fundamental scientific

understanding, Systems Biology promises

practical benefits in medicine, engineering and

elsewhere. Although its potential applications

are as diverse as they are plentiful, this chapter

describes only some of them to illustrate how a

systems approach can assist in addressing

problems of great scientific and economic

importance. Such examples are intended neither

to be prescriptive nor to constrain the range of

research areas that may form the expansion of

Systems Biology in the UK.

3.2 The UK pharmaceutical sector

The UK’s pharmaceutical industry is a success

story and is second only to that of the US. It is

a significant employer of highly qualified cost-

effective R&D manpower and a consistent

major net exporter: around one in five of the

world’s top hundred medicines were discovered

and developed in the UK. Two UK companies,

GlaxoSmithKline and AstraZeneca, were second

and fifth in the 2004 world league, having 9%

and 5% of total market share respectively18

. In

addition, other global companies such as Pfizer

have a major R&D presence in the UK.

However, over the past two decades there has

been a persistent and worrying shift of

pharmaceutical R&D from Europe, including the

UK, to the US. Moreover, although an active

source and developer of new drugs, the UK’s

biopharmaceutical industry is dwarfed by its

American rival.

The pharmaceutical sector has increasingly

become reliant upon biotechnology services

and products. Over the last decade, a number

of private biotech companies, mainly based in

the US, have focused on the development of

computer models of human disease for use in

drug discovery and clinical trials. Large US

pharmaceutical companies are benefiting from

these applications by adopting a policy aimed

at buying and incorporating biotech firms into

their main business, and exploiting their

intellectual property (IP) rights: a practice that

in Europe is still uncommon.

3.3 Drug research and development

The pharmaceutical and biopharmaceutical

sectors are those likely to benefit most from

Systems Biology in the immediate future. Over

the last decade the cost of developing new

drugs has increased dramatically (Figure 3).

This has been accompanied by an increase in

the average total development time for drugs

from just over 8 years in the 1960s to just over

14 years in the 1980s and 1990s. In addition,

current estimates indicate that only 5% to 8%

18 www.abpi.org.uk

19 Windhover’s in Vivo, 2003

3. Opportunities

‘Although the road ahead is long and winding, it leads to a future where biologyand medicine are transformed into precision engineering.’

Hiroaki Kitano, systems biologist, 2002

Figure 3: Change in average cost to develop successfuldrugs over time19.

22


of Phase I projects developing new molecules

produce a marketable output, by which time

anything up to $1bn will have been spent20

.

Unsurprisingly, the pharmaceutical sector is

seeking innovative tools that could make drug

discovery and development more effective.

Systems Biology could lead to significant

economic benefit by providing applications that

anticipate project failure earlier and reduce

development times. One example of the

application of cell-based Systems Biology

estimated that it could reduce drug discovery

costs by $390m (£225m) and shorten

development times by three years for each

drug that reaches the market21

.

Over the past few decades, pharmaceutical

R&D has focused on creating potent drugs

directed at single targets. This approach was

very successful in the past when biomedical

knowledge as well as cures and treatments for

most common conditions were limited.

Nowadays, the medical conditions that affect a

significant proportion of the population in

industrialised countries are more complex, not

least because of their multifactorial nature. The

sequencing of the human genome has led to a

considerable increase in the number of

potential targets that can be considered in drug

discovery and promises to shed light on the

aetiology of such conditions. Yet, the

knowledge of the physiological properties and

the role that these targets play in disease

development is still limited.

In terms of drug targets, there is a case that

much of ‘the low hanging fruit’ was picked in

the period between the late 1940s and the mid

1980s. The decline in output of new molecular

entities and medicines (Figure 4) recorded over

the last 10 years, despite the steadily growing

R&D expenditure and significant increase in

sales, bears testimony to the fact that

advances with new targets are more difficult

and that R&D projects have become much

more prone to failure22

. Some fear that the

pharmaceutical industry may not be able to

continue in its present mode of operation if it is

to remain profitable; nonetheless, it is faced

with the challenge of identifying targets that

will result in the delivery of effective new

medicines. New tools are required to support

the development of novel and more specific

drugs and Systems Biology can assist in their

selection.

A basic problem is that the many factors that

predispose to, and cause, complex diseases are

poorly understood let alone the way in which

they interact. The very fact that there are

multiple drivers for these conditions suggests

that a reductionist approach focusing on

individual entities in isolation is no longer

appropriate and may even be misleading. It is

therefore necessary to consider ‘novel’ drugs

designed to act upon multiple targets in the

context of the functional networks that underlie

the development of complex diseases.

Many of the new developments are likely to turn

into effective medicines when combinations of

drugs are used to exert a moderate effect at

each of several points in a biological control

system. Indeed, many common diseases such

as hypertension and diabetes are already

treated with a combination of two or three

medicines hitting different targets in the control

network that underlies the condition.

Investigating the possible combinations by trial

and error in man is onerous but feasible with

two components. However, it quickly becomes

extremely complicated with three components

and well nigh impossible with four or more. It is

circumstances like this that will require a

systems approach and the use of sophisticated

and progressively refined models. Systems

Biology, therefore, promises to assist in the

development of more specific compounds and in

the identification of optimal drug targets on the

basis of their importance as key ‘nodes’ within

an overall network, rather than on the

basis of their properties as isolated components.

20 Glover, 2002

21 Butcher, 2005

22 Centre for Medicine Research, 2004

23

3 OPPORTUNITIES

Increasingly powerful drugs will be aimed at a

decreasing percentage of people and

eventually at single individuals. Modelling can

be used to integrate in vivo information across

species. Coupled with in vitro and in silico data,

it can predict pharmacokinetic and

pharmacodynamic behaviour in humans and

potentially link chemical structure and physico-

chemical properties of the compound with drug

behaviour in vivo.

Large-scale integrated models of disease, such

as diabetes and obesity, are being developed

for the simulation of the clinical effects

resulting from manipulations of one or more

drug targets27

. These models will facilitate the

selection of the most appropriate targets and

help in planning clinical trials. Coupling this

approach with pertinent genomic information

holds the promise of identifying patients likely

to benefit most from, or to be harmed by, a

particular therapy as well as helping in the

stratification of patients in clinical trials.

To use an often quoted analogy from

electronics, if the genome map has provided a

detailed parts list, physiology, aided by

Systems Biology, can provide the wiring

diagram of the functional networks that

combine to translate a molecular stimulus into

a physiological response.

23 Centre for Medicine Research, 2004

24 Madema et al., 2005

25 Madema et al., 2005

26 BioIT World, 2006

27 www.entelos.com

Figure 4: Trends in key indicators for the pharmaceutical industry 1994-200323

.

Time- and cost-effective drugdevelopmentIncreased levels of lipids, a type of fat, inthe blood are an important risk factor forcardiovascular disease. Certain drugs, likestatins, can help to reduce blood lipids. Buta more significant lipid reduction can beachieved by combining statins with otherdrugs (e.g. ezetimibe) that work in differentways.

Recently, Pfizer, a major US pharmaceuticalcompany, sought to investigate the lipidlowering effects of a new experimental drugcalled gemcabene. Early studies indicatedthat gemcabene did not lower lipids as muchas statins, so would have to be used incombination with them to be commerciallyviable

24. As part of the drug’s development,

Pfizer decided to undertake a model-basedanalysis to compare the lipid lowering effectsof gemcabene versus ezetimibe incombination with a statin

25.

The results of the modelling indicated thatgemcabene did not offer superior lipid-lowering benefits to ezetimibe when used incombination with a statin. This resultcontributed significantly to the rapid decisionto stop development of the drug.

It has been estimated that the use ofmodelling data helped Pfizer save £0.8m to£1.6m in costs and four to six monthsdelay

26.

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

200

180

160

140

120

100

80

60

R&D Expenditure Development times New Molecular SalesEntities output

Ind

ex

Year

24


3.4 Drug safety

Attrition of new compounds during drug

development is predominantly due to toxicity.

Combined with lack of clinical efficacy and

safety issues arising during clinical

development, it accounts for the failure of up

to 60% of drug development projects28

.

3.4.1 Hepatotoxicity

Drug toxicity usually involves a complex mix of

defence, injury and repair, each invoking its

own control system. At present, there is no

substitute for the study of intact animals and

man to assess the safety of medicines. One of

the greatest problems of drug safety arises

when, in response to the drug, a tiny minority

of patients suffer a very serious form of toxicity

such as severe damage to liver function,

whereas most patients tolerate it well. In many

cases, this is due to genetic variations in drug

metabolising enzymes or the immune system

that influence liver function of the individual

and the response to injury. The number of

known functional variations continues to

expand rapidly and a systems approach will be

instrumental in managing the biological

complexity.

Liver toxicity is one of the most common

factors underlying failure of drug development.

In many cases, warning signals can be

identified at the preclinical stage and steps can

be taken to avoid problems in development.

However, the liver is a complex and sensitive

organ with many critical functions, some of

which work differently in the animal models

used for drug testing. These differences mean

that, although much can be done to screen for

liver or other forms of toxicity at the preclinical

stage, the predictive power of animal models is

limited by the obvious differences that

distinguish them from human biological and

physiological systems. For instance, it has been

observed that animal models and screens failed

to predict over 30% of all cases of late-stage

clinical liver toxicity29

.

Safety remains a concern even when drugs

have reached the market, after substantial

investment has already been made: for

instance, 95 medicines were withdrawn from

the US market between 1960 and 1999

because of serious drug safety concerns30

. In

financial terms, late-stage compound attrition

due to liver toxicity can be significant: the

recent difficulties with Exanta® contributed to a

30% drop in AstraZeneca share price in 200431

.

Hepatotoxicity presents an opportunity for

companies to establish pre-competitive efforts

aimed at the development of models simulating

liver physiology. An initiative to understand

some aspects of hepatocyte function is already

underway in Germany (HepatoSys Network)

and in the Netherlands and may form part of

the future European Framework initiative32

. In

addition, Innovative Medicines for Europe, a

multilateral project under the sixth European

Framework programme involving a consortium

of companies, seeks, as one of its objectives,

to predict human hepatic toxicity of compounds

using in vitro data and genomic information. If

successful, the outcome would facilitate better

preclinical screening.

3.4.2 Cardiac toxicity

Over the last few years it has been recognised

that a number of drugs can interfere with the

electrical function of the heart causing torsade

de pointes, a potential life threatening cardiac

arrhythmia. These drugs come from diverse

pharmacological groups, ranging from

terfenadine, an antihistamine, to grepafloxacin,

an antibacterial. Because of concern about the

potential seriousness of this effect, regulatory

authorities recommend that almost all new

medicines be tested on special types of isolated

cell (in vitro), in intact animals and in human

volunteers (in vivo) to see if they prolong the

electrical repolarisation phase of the heart (QT

interval).

It is well established that genetic variation in

ion channels, particularly the potassium

28 Schuster et al., 2005

29 Sigman, 2003

30 Academy of Medical Sciences, 2005

31 Financial Times, 2005

32 www.systembiologie.de/en/index.html

25

3 OPPORTUNITIES

channel, causes predisposition to torsade

although this affects different people to different

degrees. The practical importance of this

problem, and the rapidly advancing state of

knowledge about the physiology of the heart,

makes this an ideal subject for a concerted

approach through Systems Biology. This could

bring together knowledge of the clinical factors

that predispose to the ‘long QT’ associated with

torsade, the electrophysiology of the heart,

information about molecular configuration of the

channels and genetic variants, medicinal

chemistry expertise about the interaction of

drugs with the channels and, finally, a range of

mathematical and engineering analytical and

modelling skills. The heart model developed

within the context of the Human Physiome

Project is leading the way and its adoption by US

and European regulatory bodies in the

assessment of new compounds reflects the

importance of the problem as well as the

efficacy of the technology and the approach

employed to develop it.

3.5 Animal testing

As mentioned previously, the main uses of

animal testing in industry are to model human

diseases and to investigate drug safety. Systems

Biology requires large amounts of experimental

data to make problems tractable and modelling

feasible, and it would be misleading to imply

that Systems Biology will significantly reduce the

use of animals in the short-term. However, if

increasingly accurate predictions can be made

about disease responses and drug safety by

means of in silico experiments, fewer animal

experiments may be needed to verify them.

3.6 Personalised healthcare

Traditionally patients are diagnosed and treated

as if they belong to homogenous groups within

disease catergories. With the development of

multiple sources of detailed clinical information

about the disease phenotype and the increasing

importance of genomic, proteomic and metabolic

profiling, it is likely that future developments will

place ever greater emphasis on individual risk

assessment and treatment selection. Figure 5

shows that synthesis and sequencing

productivity are increasing at least as fast as

Moore’s law33

. Some commentators suggest

that by 2050 it will be possible to sequence an

individual’s entire genome for around £100,

about the same cost as a CT or MRI scan

today34

.

Systems Biology will undoubtedly be key in the

move towards more individualised medicine by

helping to translate some of the descriptive

biomedical information into functional

knowledge. For instance, it might facilitate

analysis of the vast quantities of biological data

gathered during late stage clinical trials in

order to explain the unusual responsiveness of

some patients to a drug. However, it must be

acknowledged that the challenges facing

personalised medical care are formidable both

in terms of cost and organisation. For practical

reasons most clinical trials of therapeutic

interventions of all kinds, not just new

medicines, deal with patient populations that

have been carefully selected as being free of

other diseases or active treatments that might

complicate interpretation of the results. Away

from these trials the reality is very different.

Most patients requiring therapeutic

interventions are older than those selected for

trials and multiple simultaneous treatments are

the rule rather than the exception. A male,

aged 65, taking medication for raised blood

pressure, raised cholesterol and prostate

problems, is commonplace. His female

equivalent might substitute a treatment for

osteoporosis for that for prostate problems but

be on the same medicines for blood pressure

and blood lipids. If either has arthritic pain, a

non-steroidal anti-inflammatory will be added

as a fourth component. If one or the other has

asthma, chronic bronchitis or diabetes – all

common diseases – a fifth medicine will be

included in the cocktail. In addition, non-

medical treatment may also involve dietary

change, weight reduction, increased physical

exercise, reduced tobacco and alcohol use. The

33 Carlson, 2003

34 Dawkins, 2003

26


35 Carlson, 2003

number of permutations and combinations

rapidly becomes very large and confusing for

both patient and doctor, and it is about to

become even more complex as identified

genetic factors predisposing to disease, or

affecting the choice of treatment, increase in

significance. Even the best doctors find this

complexity difficult to handle well and elderly

patients readily become confused with the

multiplicity of medical interventions and advice

received: their adherence to treatment is poor,

the full benefits are not delivered and the

financial resources are used sub-optimally.

Given the wealth of knowledge and the vast

number of variations possible within the human

genome and the environment, only a limited

number of options exist to deal with all the

information available. One possibility is the

creation and use of a vast array of stored

information in the form ‘It is risky to give drug

Y to a patient with polymorphism X or

intercurrent disease Z’. However, this approach

is almost useless for making predictions about

complex conditions, which are often unique to

the patient under examination, and is likely to

overwhelm practitioners and researchers with

numerous and redundant low relevance

warnings. Alternatively, Systems Biology could

be used to help understand the mechanisms

that underpin human biological function so that

treatment can be matched to the individual

circumstances and genetic make up of the

patient.

However, the promise of personalised

medicines is still a widely debated issue and a

large divide exists between those who are

enthusiastic about it and the sceptics who

believe that it is still a remote possibility. For

instance, a recent Royal Society report

concluded that it was unlikely that

Figure 5: On this semi-log plot, DNA synthesis and sequencing productivity are both increasing at least as fast asMoore’s law (upwards triangles). Each of the remaining points is the amount of DNA that can be processed by oneperson running multiple machines for one eight hour day, defined by the time required for pre-processing andsample handling on each instrument. Not included in these estimates is the time required for sequence analysis. Forcomparison, the approximate rate at which a single molecule of Escherichia coli DNA Polymerase III replicates DNAis shown (dashed horizontal line), referenced to an eight hour day

35.

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1970 1975 1980 1985 1990 1995 2000 2005 2010Year

109

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1000

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27

3 OPPORTUNITIES

pharmacogenetics, one aspect of personalised

medicines, would have an immediate impact on

clinical practice, with its true potential not

becoming apparent for another 15-20 years36

.

3.6.1 Biomarkers and imaging

Biomarkers are biological indicators that are

used to assess the biological state of an

organism, the progression of a disease or the

effect of treatments. Blood pressure and heart

rate, for instance, are simple indicators of

cardiovascular function. New and more complex

biomarkers include biological molecules such as

the tumour specific carcino-embryonic antigen

that can be used to track progression of colon

cancer. In some cases, multiple biomarkers are

used in risk assessment. For example blood

pressure, LDL cholesterol, blood sugar predict

the risk of a myocardial infarction. There is

currently great interest in the potential of new

indicators that have been discovered using

methods such as gene expression and

proteomics. However, the interpretation of their

significance will have to take account of

physiological and pathophysiological variability

and the extent to which they are linked to

disease mechanism. In many cases, patterns of

changes in a number of biomarkers, rather than

the biomarkers themselves, whose function

may remain unknown, are used as biological

indicators. In order to use biomarkers to their

greatest effect, a correct definition of their

reading and their appropriate qualification will

be essential and Systems Biology has the

potential to provide the right tools to do so.

Imaging techniques, similar to biological

indicators, are instrumental in allowing insight

into healthy as well as diseased biological

systems and will enable advances in the

pursuit of personalised medicine. Such

technology allows medical imaging of

molecular and pharmacological processes

directly in patients: this is already practicable

with positron emission tomography (PET) but

rapid development of molecular imaging using

magnetic resonance, ultrasound and optical

imaging techniques is also taking place.

3.7 Complex diseases and scientificproblems

Systems Biology is arguably the only research

approach that has the potential to disentangle

the multiple factors that contribute to the

pathogenesis of many common diseases. For

example hypertension, diabetes, obesity and

rheumatoid arthritis are known to be

polygenetic in origin although individual genes

may not have been identified. Ultimately, the

prevention of these conditions rests upon a

comprehensive approach that engages with

each of the more important predisposing

factors, genetic and environmental, that

operate upon individuals. A systems approach

is already proving valuable in the study of

complex scientific subjects and the research

aimed at the prevention and management of

medical conditions. Illustrative examples

explored in the following sections are:

neuroscience, cancer, ageing and infectious

diseases.

3.7.1 Neuroscience

The ultimate objective of neuroscience is to

gain insight into higher cognitive functions and

human behaviour. While Systems Biology has a

generic role to play in revealing basic cellular

properties ranging from the genome to

organelles and sub-cellular structures, in the

context of neuroscience it is at the intercellular

(synaptic), cell population and network levels

that it becomes most useful.

In the medium-term, it is probably at the level

of synapses that Systems Biology will have its

greatest impact in neuroscience. Although the

molecular biology of synaptic transmission has

been well described, the study of the

mechanisms underlying plasticity, and hence

memory and learning, is proving thornier than

expected. In part, the difficulties arise from the

copious number of proteins involved. The

investigation of the way they arrange

themselves in the synapse and the gene

expression that is responsible for their

synthesis requires firstly an understanding of

36 Royal Society, 2005

28


the function of the proteins and, subsequently,

modelling of the way in which they interact to

cause plastic changes. Modelling the

mechanisms underlying synaptic plasticity will

be key to unveiling how these changes occur.

However it is one of the greatest challenges

facing neuroscientists.

Systems Biology will also be crucial for gaining

insight into the system at the level of networks

of neural cells. Here, much is still unknown

about the coordinated functioning of cell

populations, the way in which these, as

systems, process signals and how they, in turn,

are translated into normal behaviours as well

as the pathological ones that characterise

complex diseases such as dementia,

depression, schizophrenia and autism.

3.7.2 Cancer

Cancer is a molecular disease that involves

mutations (usually more than one) in genes

that control cellular division or death.

Molecular biology is having spectacular success

in defining the exact mutations that may, for

example, cause uncontrolled cellular division

and growth. Hence, the treatment of cancer is

evolving away from the traditional method of

using highly toxic drugs in maximum tolerated

doses towards an approach that is highly

targeted to specific defects. A timely example

is provided by the use of the antibody

Herceptin® to treat breast cancer characterised

by the over-expression of the HER2 protein.

Tumours can be effective at eluding

interventions aimed at destroying them. For

instance, some cancers express factors that

eject drugs from the tumour cells, thus

preventing their action. However, cancer cells

need a blood supply to divide and grow and

this need is being exploited by specific drugs

that inhibit the growth of blood vessels into

tumours. Treatment of cancers must be

monitored and imaging technologies are key in

assessing the response of tumours to

treatment. In particular, methods that measure

blood flow or metabolism are giving much

earlier assessment of tumour response than

the standard way of measuring tumour size.

The tracking and the modelling of factors that

influence drug delivery and penetration, and

tumour response are critical to the

understanding of cancer mechanisms and their

treatment: Systems Biology is the approach

most likely to succeed in this endeavour.

3.7.3 Ageing

Developed countries around the world are

observing a significant increase in life

expectancy. Longevity, however, is not always

accompanied by a corresponding increase in

quality of life, a mismatch that is stretching the

resources of national health services. For

example, age-related loss of mobility is often

associated with musculoskeletal problems

including the gradual loss of muscle mass

(sarcopenia), bone thinning (osteoporosis) and

degeneration of joints (osteoarthritis). These

conditions cannot currently be prevented but

some can be delayed, and to some extent

reversed, by treatment. This requires a sound

understanding of the processes underlying

ageing but their intrinsic complexity, involving

multiple mechanisms with effects at multiple

physiological levels, is presenting researchers

with considerable problems.

Research is helping to develop a hypothesis

concerning the genetic basis of ageing and the

mechanisms involved. One theory suggests

that ageing is due to gradual accumulation of

cellular damage leading eventually to

functional impairment of older tissues and

organs37

. Genetic effects on the rate of ageing

are mediated primarily through genes that

influence somatic maintenance and repair and

which may respond to environmental cues,

particularly the level and quality of nutrients.

The concept of ageing as an accumulation of

damage at multiple points, each injury making

only a modest contribution to the whole,

suggests that reductionist studies will fail to

capture the essence of what drives the ageing

process and thus illustrates the need for a

systems approach.

37 Arking, 1998

29

3 OPPORTUNITIES

3.7.4 Infectious diseases

The spread of infections and the ability of

pathogens to deploy strategies that minimise

or defeat host defences against them are

issues that demand a systems approach.

Knowledge of the means by which organisms

exploit weaknesses in host defence systems is

increasing rapidly. Some viruses (e.g.

influenza, HIV) take advantage of rapid

mutation to evade immune surveillance or drug

action. The Epstein Barr virus (infectious

mononucleosis and Burkitt’s lymphoma),

tuberculosis bacterium, malaria parasite and

even some strains of streptococci are all

examples of common pathogens that have

developed strategies to evade or neutralise

host defence. The difficulty of dealing with

these infections is testimony to the gravity of

the clinical problem that pathogens create.

Studies of infections require a combination of

knowledge of the pathogen, the host, the

environment and the available treatments. It

will only be possible to manage such a wealth

of information using a systems approach.

Problems of hospital-acquired infections such

as MRSA or Clostridium difficile, for example,

are suitable subjects for a systems-based

enquiry.

Epidemiology makes extensive use of

predictive modelling. Indeed, one important

application of Systems Biology in the public

health arena is through complex stochastic

models that have been developed to support

planning for the control of a novel influenza A,

the agent responsible for flu pandemics. Such

models use ‘individuals-based’ simulation

approaches for the 60 million UK inhabitants,

while taking account of detailed studies of

population movement and mixing in the

country. Computational problems such as this

are very complex and require novel

interdisciplinary approaches to blending

biological, clinical, epidemiological,

demographic and behavioural data. They can

therefore benefit from the tools that Systems

Biology can provide.

3.8 Prevention versus treatment

Notwithstanding the hugely important role that

Systems Biology plays in understanding

disease and designing drugs that treat them,

the greatest opportunities may lie in health

maintenance and disease prevention. The

second Wanless report and subsequent

Department of Health White Paper on

‘Choosing Health’ identified prevention as a key

component of future public health strategy38, 39

.

Even modest measures that could retard the

effect of ageing on brain, heart, bones, joints

and skin would have a large impact on the

quality of life and future healthcare demands of

older people and consequently on the provision

of health services. Young people are vulnerable

too. Multifactorial diseases such as diabetes

and obesity are becoming prevalent in younger

people and unless effective measures are taken

to prevent an early and significant decline in

their health, healthcare demand will increase

exponentially.

It is apparent that multiple and diverse factors

interact in determining health, quality of life

and ageing. These include genetic make up,

diet, physical activity, stress, smoke and

alcohol, therapeutic and social drugs, housing,

pollution, education, and only a systems

approach will permit the understanding of how

best to prevent and delay health decline.

3.9 Synthetic Biology

Synthetic Biology is an emerging area of

research that aims to design and manufacture

biologically based devices and systems that are

not naturally available, including the re-design

and fabrication of existing biological systems.

The foundations of Synthetic Biology lie in the

increasing availability of complete genetic

information for many organisms, including

humans, and the ability to manipulate such

information using genetic engineering to

produce novel outcomes. More specifically,

engineering principles, including systems and

signal theory, are employed to define biological

38 Wanless, 2004

39 Department of Health, 2004

30


systems in terms of functional modules

through the construction of an inventory of

‘bioparts’40

. These can then be reassembled

into novel devices, acting as components for

new systems in future applications.

Whereas Systems Biology focuses on the

comprehensive study of natural biological

systems, often within a biomedical context,

Synthetic Biology seeks to build novel and

artificial biological systems and it is, therefore,

described as the engineering application of the

biological sciences rather than an extension of

bioscience research.

The relationship between Synthetic Biology and

Systems Biology can, perhaps, best be

represented by a hierarchical structure (Figure

6) showing how Synthetic Biology builds upon

Systems Biology. The basis of quantitative

Systems Biology lies in the application of

engineering systems and signal theory to the

analysis of biological systems (Level 1). This

allows the definition of systems in terms of

mathematical equations, often as individual

functional blocks known as transfer functions.

Defined systems can then be reduced (Level 2)

to bioparts and such a process constitutes a

core feature of Synthetic Biology. The function

of each biopart is expressed in terms of

accurate input/output characteristics: these are

described on a standard specification sheet,

which system designers can use as reference.

Bioparts are listed in inventories and can be

combined into devices and finally into systems

(Levels 3).

As standard engineering devices, such as

oscillators, can be built for use in fluidics,

pneumatics and electronics, biologically based

oscillators can equally now be realised in terms

of protein concentrations. Tolerances are built

into the design of any engineering part, device

or system to compensate for imperfections in

the manufacturing. Bioparts tend to have wider

tolerances than standard engineering parts and

biologically based devices are designed to

accommodate such features.

The sections that follow describe examples of

possible developments that may characterise

the field of Synthetic Biology over the next

decade and beyond. However, it is important to

emphasise that although Systems Biology is

40 A biopart can be described as the minimum amount of DNA required to fulfil a function. The DNA can either be naturally available or artificiallyassembled in sequences that do not occur in nature. Devices or composite parts are described (in a registry of parts) as comprising multiplebioparts. Devices can be combined to form systems.

Figure 6: How Systems and Synthetic Biology build upon foundations provided by engineering systems theory,signal theory and basic biomedical sciences.

Systems BiologyHealthcare Applications

EngineeringSystems andSignal Theory

Systems Biology

Synthetic BiologySynthesis of Engineering

Devices and Systems – and Industrial Applications

Biology and BasicMedical Science

Synthetic BiologySystems, Devices, PartsEngineering Specification

The Hierarchy of Synthetic Biology and Quantitative Systems Biology

Level 3

Level 2

Level 1

Next 10 years

and beyond

Now

31

3 OPPORTUNITIES

likely to yield prolific biopharmaceutical and

biotechnological developments in the

immediate future, the application of Synthetic

Biology to more general areas of industry is, at

present, more speculative. Nevertheless, it is

envisaged that the field will develop and the

areas of application become more clearly

defined. If these developments take place,

they will be likely to attract significant amounts

of commercial investment.

3.9.1 Chemical engineering

In the 19th century, chemists learned how to

synthesise compounds that had hitherto only

existed in nature. This was extended in the

20th century to the development of plastics and

other materials, which now find extensive use

in most industrial sectors. Today’s chemical

industry, which relies on oil for the

manufacturing of a considerable fraction of its

products, is likely to gain significant benefit

from Synthetic Biology. As oil reserves diminish

and both demand and price increase, scientists

are looking at more sustainable energy sources.

For example, the possibility of creating fuel by

using cell-based processes that rely on glucose

as their energy source. The least complicated

method to produce bioethanol (a type of

biofuel), for example, involves the use of

biomasses containing monomeric sugars, which

can be fermented directly to ethanol. Sugar

cane and sugar beet are biomasses that contain

substantial amounts of monomeric sugars and

were extensively used in the first half of the

20th century for the production of industrial

grade ethanol via the fermentation of molasses.

Synthetic Biology techniques have the potential

for optimising glucose dependent cell-based

processes. While acknowledging that the

quantity of fuel so produced will never be able

to meet the global energy demand, it will

undoubtedly be sufficient to contribute towards

filling a significant portion of the market.

3.9.2 Materials

An important application of Synthetic Biology

involves the harnessing of biological processes

(on an industrial scale) to produce new

materials. In many industry sectors there is a

pressing need to use very strong but extremely

light materials. In aircraft design, for example,

a significant lessening of the weight of

aeroplanes would immediately result in a

reduction of fuel consumption. Thus,

knowledge and manipulation of the biological

processes that control the production of such

materials, via a combination of Systems

Biology and Synthetic Biology, could result in

the synthesis of a whole range of novel

materials that could see significant innovation

in several industry sectors such as civil

engineering, aeronautical engineering and the

automotive industry.

Many of the desired properties described above

characterise some of the natural materials.

However, these are available in quantities that

are too limited to be considered for industrial

purposes. Engineers have tried to replicate

naturally occurring designs, in many cases

successfully. One example can be found in the

area of synthetic structural composites where a

considerable amount of work has been done on

mollusc shells, which are particularly tough41

.

Here, the architectural configuration and

material characteristics of the shell have been

copied to build synthetic structural composites.

Another example is the Golden Orb spider,

which makes the largest and strongest web.

Indigenous populations in the South Pacific

have long used the silk of the web to make

fishing nets and traps, and at least one

company is now using biotechnology

techniques for the production of strong silk

identical to that of spiders42

. Thus, if cellular

activity could be exploited, the synthesis of

new materials by means of Synthetic Biology

applications would become feasible and could

be made accurate and efficient.

3.9.3 Biologically based electronics and

computing

As discussed in the introductory part of this

section, the core of Synthetic Biology rests in

the construction of biologically based parts,

41 Mayer, 2005

42 ScienceNewsOnline, 1996

32


devices and systems which, in many cases,

conform conceptually to their engineering

equivalents. Electronics and computing are no

exception to the applications of Synthetic

Biology. However, it must be pointed out that

the operating speeds, time constants and

power consumption of biologically synthesised

‘electronic’ parts and devices are likely to be

very different from silicon based electronic

devices and computers. For example,

biologically synthesised devices may be

operationally much slower than their electronic

equivalents. However, this may be an

advantage if such devices are to be used to

monitor biological processes as, for example,

the time constants of the devices would match

those of the environment in which they would

operate. In addition, they may be driven by

power supplies that derive their energy from

the surrounding environment. Biologically

synthesised devices may also be capable of

operating in environments that would be

inhospitable to their electronic counterparts.

3.9.4 The US lead

Whereas Europe is just beginning to foresee

the potential of Synthetic Biology, most of the

important activity to date has occurred in

leading US universities and research

institutions. These, for example the Caltech

Center for Biological Circuit Design, are

investing directly in Synthetic Biology research

and education. Similarly, UC Berkeley, UC San

Francisco and the Lawrence Berkeley National

Laboratory have together started a Department

of Synthetic Biology. MIT hosts a Synthetic

Biology working group, runs Synthetic Biology

modules as part of its new undergraduate

biological engineering course and has produced

a registry of standard bioparts. Harvard’s

undergraduate course on molecular and

cellular biology offers a one year Synthetic

Biology track.

US Federal Research Agencies are also now

providing significant financial support in the

field. The National Science Foundation (NSF)

will announce a Synthetic Biology Research

Centre, worth about $40m, in the near future;

the US Department of Energy will shortly

launch a programme valued at $700 million for

research in renewable energy sources involving

Synthetic Biology applications. Both the NSF

and National Institute of Health (NIH) are

providing awards for young investigators to

pursue research in the field. Significant

investments have also come from corporate

and private sources: Microsoft has donated

approximately $700,000 to partly fund the

International Genetically Engineered Machine

Competition; Codon Devices Inc. have raised

$14m to develop the next generation of DNA

synthesis technology, and Synthetic Genomics

Inc. has made available approximately $30m

for research in the area.

33

4 THE CURRENT STATE OF SYSTEMS BIOLOGY IN THE UK

4.1 Introduction

With the aim of sketching a national vision for

the future of Systems Biology, the Academies

surveyed the current state of developments in

the field within the UK and in some overseas

countries. Evidence was sought from Research

Councils, universities, medical research charities,

government, medical Royal Colleges, Scientific

Societies and industry. Although the Academies’

investigations were not exhaustive and may

have missed individual initiatives, in aggregate

the evidence collected provides a useful

indication of the state of Systems Biology in the

UK and abroad.

4.2 Centres

The most substantial systems biology initiative

in the UK is the BBSRC/EPSRC Centres for

Integrative Systems Biology (CISBs)43. Two

funding rounds in 2005/6 saw a total of nearly

£47m divided between the six centres at UK

universities judged to have the vision, depth of

knowledge, breadth of intellectual leadership

and research resources to integrate traditionally

separate subjects in top class interdisciplinary

research programmes. Although most funding

was provided by the BBSRC, about a sixth of

the total was granted from the EPSRC to

facilitate the integration of engineering,

mathematics and physical sciences with the life

sciences. After the first five years, the costs of

supporting the centres are expected to be met

by the host universities, although they are

committed to providing some direct and indirect

support from the outset. In the future, the

Academies hope to see much greater

involvement by other biomedical research

funding bodies (e.g. MRC, NHS R&D, Wellcome

Trust, Cancer Research UK and others) as part

of the national initiative recommended in this

report (see Chapter 5).

The research focus of the CISBs reflects the

remits of the BBSRC and the EPSRC,

concentrating on biology at the molecular and

cellular level in plants, micro-organisms and

animals as well as humans. The principal

research directions of the centres announced

after the first round of CISB funding focused on

host-pathogen interactions of micro-organisms

(Imperial College), basic cell function in yeast

(University of Manchester) and ageing/nutrition

(Newcastle University)44

. The Oxford Centre for

Integrative Systems Biology that focuses on

cellular signalling provides an example of a

CISB supported by the second round of

funding. Further information about selected

existing and planned centres in the UK can be

found in Table 1.

A number of UK universities have established

systems biology research centres outside the

BBSRC/EPSRC initiative. Like the CISBs, many

are relatively new and focus on basic science and

low spatial levels: the main research theme of the

nascent Cambridge Systems Biology Centre

(CSBC) investigates signalling pathways in the

model metazoan Drosophila melanogaster, while

the new Cardiff Centre for Systems Biology

describes biodiversity, predictive cytomics and

transcriptomics as its principal research themes45.

Although many systems biology centres focus

on research at the molecular and cellular level,

some apply systems approaches to tissues,

organs and organisms. The Universities of

Nottingham and Leeds have, or are planning,

two centres apiece, each focusing on different

aspects of Systems Biology46

. The Nottingham

Centre for Integrative and Systems Biology in

43 www.bbsrc.ac.uk

44 www3.imperial.ac.uk/cisbic, www.mcisb.org/, www.ncl.ac.uk/cisban/

45 www.camsysbiol.org/, www.uwcm.ac.uk/cisb/

46 www.nottingham.ac.uk/, www.leeds.ac.uk/

4. The current state of Systems Biology in the UK

‘Life is a relationship among molecules and not a property of any molecule’

Linus Pauling, Nobel Laureate in Chemistry, 1962

34


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35


Medicine (NCISBM), for example, employs

systems and network based approaches to

address questions of clinical relevance,

including arterial hypertension, sepsis, muscle

atrophy, growth and metabolism, and

nutritional genomics47

. Although not exclusively

dedicated to systems biology research, the

Centre for Mathematics and Physics in the Life

Sciences and Experimental Biology (CoMPLEX)

at University College London hosts a DTI

Beacon Project (see section 4.6), a

collaborative study in computational biology

that seeks to build a model of the human liver

by composing models of biological entities

down to the level of cells48

. Both NCISBM and

CoMPLEX were established prior to the CISB

initiative.

Dedicated academic centres rarely encompass

all of the systems biology activities being carried

out within the host university. Many have

outreach programmes aimed at facilitating

interactions with other researchers within the

institution. These schemes include seminars and

research days such as those organised for the

opening of the CISBs. Other methods include

‘hotel style’ research facilities such as those

offered at CSBC. A novel idea pioneered by

Newcastle University consists of a dedicated

Systems Biology Resource Centre to help

develop Systems Biology in other areas of life

sciences research, alongside the BBSRC/EPRSC

Centre for Integrated Systems Biology of Ageing

and Nutrition (CISBAN)49. At some institutions

the dedicated centre is explicitly tasked with co-

ordinating systems biology activity across the

university. But in other cases, like Manchester,

centres are also part of, or closely associated

with, broader interdisciplinary life science

research initiatives50.

Not all universities are taking the centres route.

An interesting initiative is planned at the

University of Liverpool. This has established a

virtual Centre for Biocomplexity that links four of

the six faculties potentially incorporating around

70% of academic staff who, between them,

have collected £27m total grant income since

2000. Interactions across the university will be

facilitated through a comprehensive programme

that includes workshops, newsletters, a website,

videoconferencing, seminars and conferences.

The Academies were heartened to discover the

substantial amount of work being carried out in

the field of Systems Biology within the UK,

although activities are fragmented and in need

of resources and coordination.

4.3 Capacity building

The EPSRC Life Sciences Interface Programme

has established nine doctoral training centres

(DTCs) to prepare scientists with the skills to

apply engineering, mathematics and physics to

the challenges of modern medicine and

biology51

. The scheme has been set up in

collaboration with other Research Councils

(BBSRC, MRC and NERC) and although it

covers the interface between the life sciences,

engineering and the physical sciences, most

centres, however, have a substantial systems

biology component with applications at

different spatial levels. Each centre has been

awarded £1m-£1.5m to support up to five

annual cohorts of a maximum of 10 students.

In their responses to the Academies’ call for

evidence many of the systems biology centres

discussed above expressed an interest in

bidding for DTC status.

A second initiative that could support the

education and training of systems biologists

involves the Integrative Mammalian Biology

Capacity Building Awards. Integrative biology is

the study of how gene products integrate into

the function of whole tissues in intact organisms.

Understanding gene function in humans and

other mammals ultimately requires mammalian

models. The information that these can provide

is central to the development of new therapeutic

approaches to tackle human and animal

47 www.nottingham.ac.uk/cisbm/index.php

48 www.ucl.ac.uk/CoMPLEX/, www.beaconprojects.org.uk/

49 http://bioinf.ncl.ac.uk/sbrc/

50 http://193.60.152.78/

51 www.epsrc.ac.uk

36


diseases and to help deliver safe and effective

medicines. The awards are jointly funded by the

BBSRC, BPS Integrative Pharmacology Fund

(AstraZeneca, GlaxoSmithKline, Pfizer), HEFCE,

MRC and SHEFC52. To reverse declining UK

capacity in this very important field a total of

£12m has been made available for four awards.

The joint MRC, BBSRC and EPSRC Discipline

Hopping Awards represent another cross-

council initiative that can support systems

biology capacity building53. The objective of

these awards is to provide short-term support

to facilitate new collaborations between

engineers, physical scientists and life scientists,

with the aim of fostering long-term interaction.

The scheme allows life scientists to apply for

funding to investigate and develop ideas, skills

and collaboration in the physical sciences and

vice versa. As a result of a recent DTI Foresight

project54, these awards have focused on

cognitive systems, the study of which requires

a systems approach. In addition, the MRC in

collaboration with the EPSRC, offers smaller

Institutional Bridging Awards55

to develop

collaborative research programmes between the

physical and life sciences as well as a joint

training scheme with the US National Institute

of General Medical Sciences in computational

biology56. Systems biologists can apply for

these three types of award but they are not

aimed exclusively at them.

4.4 Other funding

Of all UK research funders, the BBSRC has

invested the most resources directly into

Systems Biology. As of spring 2006 its Oasis

database indicates that it has invested at least

£7.6m in grants for Systems Biology, excluding

the initiatives discussed above and those at its

research centres. Research described as

‘theoretical biology’ and ‘integrative biology’

represents approximately £6m of additional

grants. The BBSRC has also supported around

£170m of research underpinning Systems

Biology, most significantly through the genome

sequencing projects, as well as at least £38m

for post-genomic science. Moreover, a sum of

£30m has been committed to further establish

systems biology research in universities and

institutes.

In addition to the DTCs initiative described

above, as of spring 2006 the EPSRC grant list

indicated that it provided £6.3m of grants

described as ‘Systems Biology’, principally

through academic fellowships. Grants labelled

as ‘integrative biology’ as well as relevant

grants defined as ‘modelling’ total about an

additional £4.2m. Elements of the EPSRC’s

Complexity Science work stream, worth just

over £1m, also overlap with Systems Biology.

The Academies are also aware that the EPSRC

and the BBSRC have been considering

supporting the development of technical

applications for research in Systems Biology.

In addition to its involvement in some of the

initiatives mentioned above, the MRC supports

the Oxford Heart Physiome project and some

independent systems biology research. The

MRC’s particular interest in Systems Biology

lies between the levels of the cell and

organism. Evidence submitted to the

Academies highlighted work in neuroscience,

biostatistics, enabling technologies, post-

genomics and elsewhere. The Wellcome Trust

supports some systems biology research,

including projects such as the Heart Physiome

Project and the Integrative Animal and Human

Physiology Initiative57

. Evidence from medical

research charities such as the Arthritis

Research Campaign, British Heart Foundation

and Cancer Research UK indicates that

Systems Biology is becoming an increasingly

important component of their research

programmes. The Department of Health

reported a nil return on systems biology

research conducted by its R&D Policy Research

Programme and by NHS R&D programmes.

52 www.mrc.ac.uk

53 www.mrc.ac.uk

54 www.foresight.gov.uk

55 www.mrc.ac.uk

56 www.mrc.ac.uk

57 www.wellcome.ac.uk

37


4.5 Industry

Systems Biology is being applied in many

industrial sectors including pharmaceuticals,

biopharmaceuticals, biotechnology, food and

personal care, some of which are outside the

scope of this report. Based on the evidence

received by the Academies, companies that

have adopted Systems Biology in their

activities can be divided into two broad

categories: those that employ Systems Biology

to make end products and those that create

systems biology tools, which are sold to, and

used by, the companies in the first group.

Many Small and Medium sized Enterprises

(SMEs) in the biotech sector for example,

belong to the latter category and, mainly in the

US, seek to license their tools to larger

pharmaceutical firms.

Some confusion exists about the understanding

of ‘Systems Biology’, as it is often interpreted

as a purely informatics solution to the question

of biological complexity. Currently, only a few

companies are putting the core concept of

Systems Biology properly into practice by

informing their research through the iterative

cycle between experimentation and modelling.

For instance, a substantial number of

companies principally focus on informatics

tools and undertake little experimental activity.

Also, in sectors that rely on external

partnership, such as biotechnology,

multidisciplinary teams are uncommon. In

contrast, the exchange between biological

experimentation and computational modelling

occurs routinely in large pharmaceutical

companies. Here, multidisciplinary teams,

where life scientists, engineers and physical

scientists work together, are the norm.

The majority of the universities that provided

evidence expressed a desire to collaborate with

industry. Many academic-industrial

collaborations are in the pipeline although only

a minority have been finalised. Researchers

from the six BBSRC/EPSRC centres are being

invited to participate in a second initiative,

worth a total of £5m, which aims to help UK

bio-industries exploit the cutting edge

expertise and facilities in the centres.

Academia-industry collaboration has been

promoted through industry funded academic

posts, such as the AstraZeneca Chair of

Systems Biology at the University of

Manchester, or industrial ‘clubs’, such as that

established at Imperial College. A few

universities also identified systems biology

related spin-out companies or industrial

secondments, placements and training. The

majority of the university responses mentioned

IP policies, although none were specific to

Systems Biology. Universities tend to retain

ownership of the IP created by their staff but

provide incentives for inventors and

researchers to generate IP. Most institutions

mentioned some kind of commercialisation unit

or subsidiary company with the task of dealing

with IP issues, amongst other matters.

4.6 DTI Beacon Projects

In 2002 the DTI BioScience Unit launched an

initiative aimed at promoting collaborations

between industry and academia to create a

critical mass in the field of Systems Biology in

the UK58

. The initiative is supported by a

budget of £8m and involves several companies,

including Microsoft, Unilever and Pfizer. The

projects are ambitious and combine world-

class, cutting-edge science with the potential

to deliver wide-ranging benefits to industry

including:

• Imaging changes in disease.

• Computer models to predict drug action.

• New rapid approaches to detecting diseases.

• Computer models to detect toxicity.

• Biochemistry in silico.

• Seeing genes in action.

As Systems Biology falls within the remit of the

DTI’s Technology Programme, it could be

identified as a focus for future collaborative

R&D support or a Knowledge Transfer Network.

58 www.beaconprojects.org.uk/

38


4.7 Medical Royal Colleges andScientific Societies

Our survey of medical Royal Colleges indicated

that they are not involved in this activity

perhaps reflecting their preoccupation with

specialist training and the quality of specialised

clinical services. Scientific Societies, on the

other hand, expressed greater interest. The

activities being undertaken are principally

organised in the form of scientific meetings,

such as the Royal Society of Edinburgh’s one-

day conference on mathematical biology in

2005, or new journals, such as the Institution

of Engineering and Technology’s (formerly the

Institution of Electrical Engineers) ‘Proceedings

in Systems Biology’ of the Royal Society of

Chemistry’s ‘Molecular Biosystems’. An

interesting recent development is the €250K

(~£170K) Royal Society and Academies des

Sciences Microsoft European Award for work at

the intersection between biological sciences

and computing59

.

4.8 The international picture

Currently the US leads the world in the

application of Systems Biology to high

throughput genome wide datasets. The

Institute for Systems Biology in Seattle is

probably the most advanced systems biology

centre in the world. It was co-founded by Leroy

Hood in 2000 and has now expanded to 11

groups and more than 170 staff members with

an annual budget of more than $25m60

. Other

US initiatives, such as QB3 at the University of

California, Stanford BioX and those at the

Whitehead Institute, have dedicated similar

capacity and resources to Systems Biology61

. A

recent report from the World Technology

Evaluation Centre (WTEC) highlights that the

current US lead is largely due to investment by

funding organisations and research institutions

made over the last five to seven years62

.

Whereas the US has the most significant

targeted investment in Systems Biology,

several other countries have been following a

similar trend in the last few years63

. In January

2004, the German Federal Ministry for

Education and Research funded an

interdisciplinary systems biology research

initiative, the German hepatocyte programme

HepatoSys Network, with the aim of achieving

a holistic understanding of human liver cells

biology64

. The Swiss initiative in Systems

Biology, Systems X, involves the Swiss Federal

Institute of Technology in Zurich and the

Universities of Basel and Zurich, and aims to

enhance and expand transdisciplinary research

and education at the highest level in the field65

.

Japan boasts a number of important research

initiatives, often supported through traditional

government programmes, including the Kitano

Symbiotic Systems Project, and work at Riken,

Kyoto, Keio and Tokyo Universities66

. Significant

research is also being undertaken in Australia,

Belgium, Canada, the Netherlands, New

Zealand, Singapore and South Korea.

The European Union funds several projects

concerned with Systems Biology within the

Sixth Framework Programme, for example

EUSYSBIO, DIAMONDS, COSBICS and the

BioSim Network67

. Importantly for the future,

the proposal for the Seventh Framework

Programme 2007-2013 includes significant

references to Systems Biology under the

themes of health and biotechnology. Moreover,

the European Science Foundation has identified

Systems Biology as ‘a Grand Challenge for

Europe’ that requires pan-European efforts to

meet it68

. The Federation of the European

Biochemical Societies (FEBS) disseminates

59 www.royalsoc.ac.uk/

60 www.systemsbiology.org/

61 www.qb3.org/, http://biox.stanford.edu/, www.wi.mit.edu/



64 www.systembiologie.de/en/index.html

65 www.systemsx.ch/index.html


67 Jehenson & Marcus (eds.), 2004

68 European Science Foundation, 2005

39


Systems Biology advances through its main

publication ‘The FEBS Journal’69

.

4.8.1 International collaboration

Researchers in different countries and

institutions have produced a plethora of models

to simulate various biological phenomena. Yet,

only a small proportion of these models are

accessible to those outside the groups that

developed them or have been documented in a

form other than in the scientific papers where

they were originally published70

. Much of the

promise of Systems Biology will be realised

from insights that emerge from the

combination of multiple experimental

approaches and analytical techniques. For this

to be achieved, it is essential that data are

generated in a form that is suitable for sharing

between different investigators and centres.

International collaboration will therefore be

central to the development of the field. Global

consortia have already been established to

address specific aspects of Systems Biology.

For instance, the Physiome Project seeks to

accomplish a quantitative description of the

whole human organism, while the Receptor

Tyrosine Kinase (RTK) Consortium strives to

facilitate and coordinate international efforts

for the understanding of RTK signalling

pathways and their relationship to human

pathologies71

.

International links with UK universities have

been established, often in response to pressure

from the grass roots rather than the centres.

The search for research excellence and new

academic colleagues transcends national

borders. For instance, during the preparation of

a systems biology programme targeting micro-

organisms, the German Ministry for Education

and Research accepted suggestions from

scientists that bidding should be opened up

internationally. Organisations from the UK, the

Netherlands, Austria, Spain and Norway joined

the German government in the creation of a

‘transnational funding programme’. Its first

deadline in January 2006 was met with a large

number of high quality applications. The

programme will be subsumed in the EraSysBio

collaboration which may serve as a stepping-

stone towards a substantial transnational

systems biology programme in biomedicine.

It takes more than modelling software to

connect models: the terminology used for

system components, as well as their

operational function, should be congruent.

Separate models are required to test the

diverse behaviors exhibited by a system but

also to investigate systems at different spatial

and temporal levels. Many discrete models

cannot yet be combined to effect the modelling

of larger systems. Universal standards and

protocols are yet to be set and it is likely that

these will originate from the international

systems biology consortia. It is in this context

where groups outside the US lead. For the last

five years, the Silicon Cell Initiative has been

running a website that collects models

published in associated journals and makes

them publicly available72

. The European

Bioinformatics Institute has recently started a

repository for models that aims to establish

more extensive linkage to databases73

. All

these initiatives adhere to the world-wide

standard of systems biology Mark-Up

Language, making models exchangeable in a

uniform format. Nevertheless, establishing

international standards can be time consuming

and requires collaboration between multiple

key stakeholders.

69 www.febsjournal.org/

70 Finkelstein et al., 2004

71 www.physiome.org, www.rtkconsort.org

72 www.siliconcell.net

73 www.ebi.ac.uk/services/

40


41

5 IMPERATIVES

5.1 Working across cultures

Research in the field of Systems Biology

requires close interactions and collaborations

between many disciplines that have

traditionally operated separately such as

medicine, biology, engineering, computer

science, chemistry, physics and mathematics.

Although research methods may be specific to

an individual discipline, research objectives can

be shared. There has long been recognition of

the value of interdisciplinary collaboration,

however the successful realisation of a

common research agenda has been the

exception rather than the rule.

Limited training in disciplines other than one’s

own may lead to misconceptions and

misunderstandings with regard to what

scientists from different backgrounds actually

do, how they do it and what could potentially be

achieved. Life scientists often fail to appreciate

the distinctions between the sub-disciplines

within engineering, mathematics and the

physical sciences whereas physical scientists

often react with surprise and frustration to the

fuzziness of biological concepts and data, and

the fact that biology keeps evolving. This

reflects the dichotomy between the two types of

disciplines that is principally due to the differing

nature of the problems they try to address. The

physical scientist, for instance, expends great

effort to reduce experimental variability, while

the life scientist may seek patients that show

extremes of disease susceptibility or drug

response as clues to new understanding through

genetic variations.

Important differences also exist in the

understanding of common concepts such as

‘model’, ‘elegance’ or ‘theory’, the meaning

attributed by the two classes of researchers to

such terms and the contexts in which they are

used. A simple example of a cultural barrier is

the tendency for life scientists to use a

Microsoft word processor whereas many

computer scientists use LaTex. In isolation this

would be a trivial challenge, but it is

symptomatic of deeper divisions. Hence, there

is a need to ease communication and to breach

the gap between the practices in the life

sciences and those in engineering,

mathematics and physical sciences. The

evidence submitted to the working group

revealed a host of different methods for

bringing researchers from different disciplines

together including workshops, training,

seminars and conferences. However, they need

to be applied more extensively and routinely.

Research in traditional disciplines is conducted

by reducing a problem to its elementary

components and studying each of them

separately. Reductionistic research tends to be

monothematic and therefore conducted by

scientists who are highly specialised in closely

related subjects, if not sub-specialties of the

same one. In contrast, Systems Biology

demands a focus on the problem as a whole and

therefore a combination of skills, knowledge and

expertise that embraces multiple disciplines.

However, at present, assorted teams are

unusual in academic environments but they

have to become a common feature if Systems

Biology is to advance. A good model that could

inspire the organisation of university

laboratories is provided by the research

practices of pharmaceutical companies. Here,

researchers are arranged in interdisciplinary

teams and operate in a problem-focused mode

whereby individual contributions are aimed at

advancing the progress of the team towards the

solution, rather than that of the individual

scientist.

5. Imperatives

‘The problem of biology is not to stand aghast at the complexity but to conquer it.’

Sidney Brenner, Nobel Laureate in Physiology or Medicine, 2004

42


Adapting academic research practices to

interdisciplinary trends will therefore require

the reorganisation of traditional universities,

research groups and laboratory space.

Teaching arrangements will also have to be

adjusted in order to ensure appropriate

training of future systems biologists. But more

general issues such as the Research

Assessment Exercise (RAE) and peer-review

system also need to be addressed. Finally,

research will have to be supported by

appropriate infrastructures and organised in a

manner that facilitates exchange of knowledge

and expertise between disciplines.

5.2 Infrastructure: centres ordistributed networks?

One of the major issues, fervently debated

among the experts and within the joint

Academies working group, is whether

researchers from different disciplines should be

brought together within a single physical

environment (centre) or team up as a

distributed network. Within a centre, the

opportunities for researchers to spend time

together and to interact on multiple levels are

significantly facilitated. Moreover, a shared

infrastructure that can accommodate

multidisciplinary teams may be the optimal

arrangement to provide all the tools necessary

for research in a rapidly evolving field such as

Systems Biology.

In the short-term, the advantages of a centre

are very appealing but, with suitable planning

and effort, strong integration can equally be

achieved in a distributed network. In addition,

in the medium to long-term, there is the

danger that centres may lose the vibrancy that

characterised them initially. However, as

Systems Biology is likely to become a

pervasive approach throughout science, the

expertise built in the centres will have to

become an integral part of the hosting

institution, similar to the plans drawn for the

CISB centres. Nonetheless, there is a

legitimate concern that centres may become

isolated silos and not disseminate their

expertise into the wider academic research

environment.

Dynamic and visionary leaders can gather

sufficient resources and create effective

research infrastructures both in the form of

actual research centres and distributed

networks of collaborators. However, when

considering the most efficient and rapid way to

increase the UK’s systems biology capacity in

the immediate term, there are arguments in

favour of co-location of researchers within

single large academic centres. Distributed

collaborations would still need a core to focus

their efforts. While developments in information

and communication technologies have allowed

progress in high-speed networking of data, and

facilities such as tele-conferencing have made

international exchanges much easier, close

physical proximity with informal regular

interactions is most likely to build effective

teams and result in timely research outcomes.

The conclusions of the WTEC report, discussed

in chapter 4, and the success of the

BBSRC/EPSRC’s Interdisciplinary Research

Centres lends weight to centres as a favoured,

but not exclusive, model for building up

systems biology research rapidly.

Centres are likely to be an effective model for

facilitating cross-discipline familiarisation.

Although this can be aided by formal training

programmes, much of the required

understanding develops through ‘osmosis’,

whereby time spent together opens up

opportunities for discussion and other

interactions necessary for joint research, and

provides for the understanding of the differing

research ethos, priorities, working practices and

uncertainties in each contributing discipline.

Physical co-location of researchers has merits

beyond those of facilitating cross-disciplinary

interaction. Currently, many aspects of systems

biology research require access to physically

large and expensive pieces of equipment. It

would be more efficient to centralise these in a

43

5 IMPERATIVES

few high quality facilities rather than spread

them too thinly. In contrast, some components

of Systems Biology, such as computational

modelling, are less capital-intensive and

therefore could be more distributed.

Evidence submitted to this inquiry indicated

that there was great enthusiasm for

collaborations in both industry and academia,

notwithstanding the numerous hindering

factors. Centres provide a more convenient

‘one stop shop’ for industry-academia relations

than distributed networks and might be better

able to offer the security and longer term

collaborations that industry in the UK needs.

5.3 New systems biology centres ofexcellence in the UK

As discussed in the previous chapters, the UK

already boasts a number of centres, many of

which are supported or driven by recent

BBSRC/ESPRC initiatives and focus on systems

at the molecular and cellular level. However,

additional systems biology centres are needed

to address medical or engineering problems

that do not fall easily within the remit of

existing initiatives and/or expand on

fragmented projects that have been developed

outside the BBSRC/EPSRC programmes.

Systems Biology aims to gain insight into the

functioning of organs, physiological systems

and ultimately the whole organism. The existing

initiatives are not sufficient to create the critical

mass and the knowledge base needed to

achieve this objective. Thus, the Academies

recommend the establishment of new

centres located within leading universities

that have internationally competitive

research in biology, medicine, engineering

and physical sciences. They must be a focus

of activity with effective networking to

smaller centres in other universities,

including those currently being established

by the BBSRC and EPSRC, and linked to

international initiatives. It is essential that

the centres should seek collaborations with

industry and the NHS to ensure that

projects of high national economic

importance receive priority. Systems

Biology is destined to become a pervasive

scientific approach and advancing this

objective should form part of the mission

statement of the centres. These must be

outward looking and avoid becoming

scientific ghettos. Their remit should focus

on world-class research, ranging from basic

science to clinical practice to industrial

products and include formal training and

education (i.e. Masters and PhD

programmes) in Systems Biology (including

Synthetic Biology, which involves the design

and re-design of biological parts, devices

and systems - with applications ranging

from materials with enhanced properties to

biofuels). The programme for each

individual centre should reflect the

strengths of the university (or universities)

taking part but each centre will need to

have a mixture of biology and medicine on

the one hand and engineering, physical

sciences and mathematics on the other.

Funding should be allocated on the basis of

competitive bids to Research Councils UK

and centres should be chosen to tackle a

wide range of challenging research topics.

Examples of topics which might form part of

the work of centres include: the toxicity and

safety of medicines; the function of

neuronal synapses; the growth of human

cancers; ageing and the spread of infections

in hospitals; however, this list is neither

comprehensive nor exhaustive and is not

intended to limit applicants. The example of

the BBSRC and the EPSRC might be followed

with a first phase followed by one or more

additional phases. Engineering research,

particularly in the field of Synthetic Biology,

is set to grow rapidly and must form a

significant part of the work of some of the

centres proposed in this initiative.

The new centres should network widely,

develop and spread expertise, drive the

44


creation of new methodologies, allow

researchers around the country access to these

developments and encourage knowledge

sharing. Much of the work in the field is

focused on complex problems where the goals

are ‘public’ so outcomes must be made freely

accessible. But some goals, such as the

development of new drugs, will be inevitably

‘private’. However, research at pre-competitive

levels is not commercially sensitive and,

therefore, can be shared.

The centres should be linked by the

SuperJanet5 network, hold regular electronic

conferences and one annual meeting with the

BBSRC/EPSRC centres. There is considerable

potential for sharing systems modules within

the UK network with other European centres

and world wide. The establishment of an

overarching research body (either national or

European) should be considered to assist

coordination of tasks and ensure competitive

progress. It is essential that the new centres

should seek collaborations with MRC, NHS R&D

and industry to ensure that feasible projects of

high national biomedical importance receive

appropriate priority. Pharmaceutical firms are

highly focused on specific objectives and it is

likely that, rather than working towards the

general development of a systems biology

knowledge base, they will work with both

academic centres of excellence and small

boutique firms to address particular issues as

well as develop knowledge management

systems to facilitate decision-making.

5.4 Additional investment

Systems Biology promises to improve the

health and the wealth of the nation and raise

its competitiveness to international levels. If

these opportunities are not to be missed,

significant resources must be invested in

addition to the funds that are already being

spent in the field. The Academies therefore

recommend that an investment of

approximately £325m is made over a

period of 10 years to establish three to five

new centres. This consists of approximately

£75m for initial capital costs to be spent

over the first three years, and £24m per

annum as recurrent expenditure. The size

of each centre may vary. It is estimated

that, at current prices, a centre capable of

housing between 30 and 35 scientists and

support staff, as well as up to 30 doctoral

students, would have a core recurrent

budget of £5m a year, including

consumables. Additional costs would be

incurred for equipment, constructing new

buildings or adapting existing facilities. A

capital budget of about £15m per centre

would be necessary to meet this

expenditure, although, as far as possible,

existing resources should be re-deployed

by the host university. Centres of this size

would provide sufficient capacity to work

on one major project and one or two

subsidiary projects. After 10 years

successful centres should be progressively

integrated into their host university.

The new initiative would be more costly

than the present BBSRC/EPSRC programme

because of the inclusion of projects

involving a substantial engineering and

medical component. Hence, additional

government support is needed to realise

this important opportunity for the UK.

Partnerships should also be sought to

offset part of these costs through strategic

collaborations with industry, medical

charities, the MRC, NHS R&D and the DTI.

The Academies foresee that, within the next 10

years, Systems Biology will evolve into an

essential and pervasive component of scientific

inquiry. It will provide innovative tools for the

management of complex scientific issues and

consequently reflect the quality of the work

carried out in major research institutions.

Provided that the centres pass periodic peer

review, the Academies consider that a life of

about 10 years should be sufficient to embed

them within the university research framework.

There may need to be a transitional period

45

5 IMPERATIVES

during which universities incorporate the

centres into their existing organisation,

research funding agencies ensure that their

grants committees are appropriately organised

and HEFCs adapt their research assessment

mechanisms for a better and fairer recognition

of research excellence in interdisciplinary areas.

5.5 Leadership

Lack of overarching direction often hinders

interdisciplinary research work, hence senior

academics with a strong vision will be vital to

drive Systems Biology forward. Worryingly, the

replies from the universities to the Academies’

call for evidence did not always appear to

recognise the need for strong central

leadership to overcome these problems. Only a

few of them gave specific information about

the responsibility that their directors would

have in setting the direction of systems biology

programmes, control of budgets, appointments

and promotions.

The success of leaders in the field of Systems

Biology will depend strongly on the extent to

which they accomplish the creation of the

environment that researchers need to develop

an understanding of different working cultures,

and manage also to implement strategies that

integrate these cultures into shared working

practices. Senior academics may have the

initial vision for a project in Systems Biology

but it will inevitably be the junior researchers,

and their networking with peers, who develop

the collaborative relations that eventually

deliver the results. The infrastructure and

working environment for the project must

therefore be one that generates and fuels

interaction at all levels. Junior researchers

need to be encouraged and supported to

commit time to such relations, and the

familiarity and knowledge that they gain in the

other discipline needs to be recognised.

Leaders will therefore be expected to manage

proactively the process of cross-discipline

assimilation, clarifying research goals and

preventing fragmentation.

Successful leaders often come with the most

challenging, but potentially rewarding, visions

and the ability to create excitement in a new

area. The UK has many successful academics,

but relatively few who can claim excellence in a

second discipline. In the near future, it may be

difficult to find a sufficient number of senior

group leaders able to develop interdisciplinary

teams and provide appropriate training and

career development. This issue could be

addressed by, for example, creating early and

mid-career research development opportunities

for highly imaginative and dynamic scientists

that would enable them to branch out into a

new subject area. Expansion and updating of

existing discipline hopping schemes would be

very helpful although the creation of ‘new

blood’ posts and some overseas recruitment

may be necessary.

5.6 Assessment and careerprogression

The HEFCs rightly strive to maintain the

strength of individual and well-established

disciplines but interdisciplinary research areas,

which need to be nurtured so that they can

become established and grow, can encounter

difficulties when assessed by the RAE. Unlike

much traditional research, interdisciplinary

grant proposals may fall within the remit of

two, three or even more main panels, making

it much more difficult to assess them to a

common standard, and the more disciplines

involved the bigger the problem tends to be.

Assessment criteria may differ, sometimes

profoundly, between the life sciences and

engineering, mathematics and the physical

sciences. For example, in the assessment of

mathematics less emphasis is placed on

research grant income because much of the

research is done by the individual academic

without the need for a research team, a

laboratory and specialised equipment.

Conversely, in the life sciences research

requires larger teams, a varied equipment base

and experimental animals; it is therefore more

expensive and thus leads to grant income

46


being used as a major index of success. There

is a consensus among many senior academics

that, despite some recent changes, it is simply

not possible to adapt the RAE in a manner that

will result in robust and fair assessment of

interdisciplinary activities74, 75

. The Academies

hope that the newly proposed metric-based

assessment procedures will be better designed

for the appraisal of new research trends.

In most institutions assessment procedures

determine promotions, which therefore also

tend to be subject-specific. Consequently,

researchers who engage in interdisciplinary

research may be penalised. None of the

universities responding to the call for evidence

mentioned promotion procedures specifically

designed for interdisciplinary research,

although a few, such as Newcastle, mentioned

measures for interdisciplinary staff in general.

It is therefore desirable that institutions

undertaking systems biology research consider

new mechanisms of assessment and promotion

to ensure that career progression is not

hindered by the unsuitability of assessment

procedures.

Young scientists who decide to explore a

second discipline as part of their

interdisciplinary training take disproportionate

risks with their careers. The time required to

establish themselves as interdisciplinary

researchers is prolonged by the need to master

their adopted new discipline and to develop

their thinking to the point where major

publications and funding proposals are

possible. This can lead to slower development

of the indicators that they require to

demonstrate their scientific ability: a significant

issue for both the individual and the hosting

institution in the context of the RAE.

A further barrier is that research papers in

different disciplines are subject to different

peer-review practices. Within the mathematical

and statistical sciences, for example, refereeing

a manuscript takes, on average, longer than in

the life sciences: this has a direct effect on the

pace and urgency of research. There are also

very different practices with regard to the

number of authors and the order of their

names on publications. Traditionally, in the life

sciences, the order of authorship indicates the

extent of an individual’s contribution to the

paper. This has repercussions on career

progression and assessment as the more

frequently a researcher is listed amongst the

first few authors the more successful he/she is

judged to be. Systems Biology often requires

equally important contributions from many

different researchers with different specialities

and the order in which the authors are listed

cannot, therefore, be reflective of the

importance of their work. In the particle

physics community, for example, papers

frequently have tens of authors whose

contribution is perceived as equally valuable

and little significance is attached to the order

of their names. Similar practices may be

adopted to overcome the problem posed by

Systems Biology.

Such factors and others constitute impediments

to the development of interdisciplinary research

and deter talented scientists. Individuals may

consequently decide to pursue their career

elsewhere, outside the UK or, alternatively,

choose not to explore hybrid research fields and

compromise their work within the boundaries

imposed by the traditional classification of

subjects and research areas. Circumstances

such as these are undesirable and measures

should be taken to ensure that universities

provide appropriate environments for innovative

research trends and for those scientists who

wish to embark on such developments.

The Academies therefore recommend that

universities bidding for one of the new

centres should be required to specify their

plans for addressing the structural,

organisational and human resource issues

that are known to hinder interdisciplinary

research; implementation of these plans

would be a condition of a successful grant

application.

74 Academy of Medical Sciences, 2004

75 Royal Society, 2003

47

5 IMPERATIVES

76 BBSRC, 2006

The interdisciplinarity of Systems Biology

poses a challenge to the traditional

structure of university departments and the

current arrangements of research grants

committees in the public, private and

charity sectors. Academic organisation,

funding streams and research assessment

mechanisms must be evolved to encourage

growth of interdisciplinary research

activities such as Systems Biology. This

needs to be reflected in approaches to

leadership, career development, peer

review and publication criteria. Universities

must break down barriers between

disciplines and consider new methods of

organisation that promote the development

of novel scientific approaches. A substantial

change in culture is required, in which

biology and medicine become more

quantitative. The Research Assessment

Exercise, as currently structured, continues

to be a barrier to interdisciplinary research.

5.7 Education and training

If the UK is to remain competitive in the

biomedical sciences as well as engineering,

mathematics and the physical sciences in the

21st century, the challenges of training a cadre

of researchers to deliver effectively the

necessary capability in Systems Biology need

to be addressed. Major initiatives in Systems

Biology will require a very broad base of

disciplines and associated skills but the exact

mix of talents needed will change with time.

Although the academic foundations of future

systems biology researchers are almost

certainly laid in schools, a detailed analysis of

secondary education is beyond the remit of this

report. Nevertheless, the importance of

revitalising STEM subjects in schools to ensure

the provision of sufficient numbers of high-

calibre researchers in the future is recognised.

Demonstration of the contribution that physics

and chemistry can make to biology may lead to

increased student interest in these subjects.

A similar benefit is likely to result from showing

the significant role that engineering also plays

in biomedical research.

Currently, biological and the more numerical

sciences are often taught separately. But

interdisciplinary research requires engineers,

mathematicians and physical scientists to have

a thorough understanding of biology. They

need both the expertise and the environment

necessary to think about fundamental

biological problems. Simply adding a little

biological knowledge to their background will

not be sufficient. Complementary issues arise

when considering the training of biomedical

scientists. For instance, life science

undergraduates, including medical students,

may receive some training in statistics,

occasional exposure to bioinformatics and

minimal introduction to mathematical

modelling. This is not adequate to provide

them with the skills required to engage fully in

systems biology research.

It is paramount that students who embark on

systems biology courses undergo rigorous

training. For this reason teaching, at any level,

should be delivered by the most research active

staff, among whom today’s systems biologists

are to be found. However, given the conflict

between the demands posed by teaching and

the intense pressure to produce and publish

high-quality research, universities must find

ways to ensure that research active staff who

choose to teach are rewarded appropriately.

A key question to consider is the amount of

expertise that future systems biologists will

require in a core discipline before moving into

interdisciplinary research. Most academics

need to feel ‘rooted’ within a parent discipline

because from it they derive their primary peer

support and recognition. At a recent BBSRC

meeting that considered strategies to develop

Systems Biology in the UK, many academics

and industrialists indicated a preference for

systems biologists to be trained in a core

discipline before undertaking interdisciplinary

work76

. Discipline-hopping awards can help

researchers to begin exploring a new subject.

But, in their present form, these schemes are

aimed more at familiarising the awardees with

48


the working culture of the other discipline than

allowing the researcher to acquire new skills.

It can therefore be argued that future systems

biology researchers should initially be trained

in a ‘parent’ discipline at an undergraduate

level before undertaking postgraduate systems

biology training. Nonetheless, their

undergraduate courses should also include

exposure to problems and interaction with

peers from other disciplines. For instance,

final-year undergraduate programmes, or

masters degrees, in one of the life sciences

could include discipline-hopping modules in

engineering, mathematics or the physical

sciences and vice versa.

Currently, the education and training of systems

biology researchers in the UK begins at

postgraduate level. Many of the universities

that provided evidence have, or will be,

introducing masters or PhDs in systems biology.

Interestingly, none of the universities that

responded offer whole undergraduate degrees

in the field, although a few, such as Glasgow,

are planning to offer undergraduate modules.

The tendency to establish postgraduate, rather

than undergraduate, Systems Biology courses

reflects the importance of mastering a parent

discipline before moving on to a more wide-

ranging training. Alternatively, universities may

simply be piloting Systems Biology at

postgraduate level before a wider roll out

across higher education.

Inevitably, training in Systems Biology will be

lengthy and expensive. It is a new area of

research and therefore it is difficult to single out

any one model of education and training as

superior at this early stage. Nonetheless,

rooting in a parent discipline allows the

acquisition of a thorough understanding of the

scientific method as well as providing a safe

return path. The importance of this should not

be underestimated, especially in light of the

currently uncertain career opportunities in

cross-discipline research. Indeed, systems

biologists should be given opportunities to

maintain their expertise in their parent

discipline, for example by provision of protected

time to pursue monodisciplinary research.

The UK is only now developing provision for

training in Systems Biology. The substantial

investment in DTCs that the EPSRC and the

BBSRC are leading include four-year PhD

courses. Some of these centres have taken

explicit measures to provide students with a

more interdisciplinary training. These include

‘buddy systems’ (two students, one of

theoretical and one of experimental background

running parallel PhD projects) and visits to

other collaborating systems biology laboratories

to carry out diverse work on a single project.

Nevertheless, current doctoral training

programmes will need adjustment. The training

of researchers with sufficient theoretical

background to apply and develop modelling

techniques and, at the same time, with an

adequate knowledge of experimental biology to

engage with the functionality of the data, will

require cross-discipline work and the extension

of PhD programmes to four or five years.

Students may benefit from having supervisors

in two of the disciplines that underpin Systems

Biology, for example a biologist and an

engineer, as is already the case at some of the

institutions that submitted evidence to this

inquiry77. As for the extended PhD programmes,

financial incentives will have to be made

available to attract high quality candidates and

compensate for the delays that the extra time

required to assimilate a new discipline can

cause to early career progression.

Some respondents to the call for evidence

highlighted the lack of postdoctoral training

opportunities in Systems Biology rather than

postgraduate programmes that are currently

being addressed by the EPSRC and the BBSRC.

However, others argued that postgraduate

training would meet the need provided that

sufficient research funds were available to

allow for the longer training and the time to

prepare publications.

77 A good model designed to address interdisciplinary education and training is provided by the Forum Scientium in Sweden(www.ifm.liu.se/scientium).

49

5 IMPERATIVES

5.8 The foundations of systemsbiology training

The postgraduate model of systems biology

training relies upon an appropriate supply of

undergraduates taught in the core disciplines

that underpin Systems Biology. Unfortunately

these are currently in short supply. Figures

from the Higher Education Statistics Agency

indicate that, between 1994 and 2004 the

number of graduates in engineering and

technology, and physical sciences fell by 10%

and 11% respectively78

. Similarly, in recent

years the UK’s traditional strengths in pure and

applied research in physiology and

pharmacology have declined. Both the MRC

and Wellcome Trust have expressed concern

about the decline of the physiological sciences

in the UK, particularly in terms of capacity. A

substantial number of highly skilled in vivo

physiologists will be lost to retirement in the

next five years as, among other factors, the

focus of research support has shifted towards

an increasingly reductionist analysis of

molecular pathways and their foundation in

genomics. Systems Biology offers an exciting

opportunity to revive physiology and

pharmacology before the shortage of

manpower in these disciplines begins to affect

the UK science base and industry seriously. In

its discussions with the Academies, the MRC

showed a clear awareness of the importance of

Systems Biology in rebuilding the physiological

sciences and the Academies look forward to

proposals in this area.

A recent report from the Association of the

British Pharmaceutical Industry indicated that

many science graduates lack sufficient skills in

disciplines such as mathematics, physiological

science and computer analysis, which are

important to both Systems Biology and the

pharmaceutical industry79

. One important

finding was the growing demand for

computational scientists for the analysis of

increasingly large biological and chemical data

sets using a variety of modelling techniques.

Modelling is ever more being recognised as an

integral tool within the pharmaceutical sector.

However, whereas on the one hand modellers

are more in demand, on the other, the number

of experimentalists will always have to be

higher since the collection of suitable biological

data, needed to test models, is more resource

intensive. It is the lack of proper data that

creates most bottlenecks in systems biology

research.

The growth of Systems Biology will further focus

the importance of modelling in drug R&D and

this is likely to require a shift in the way

research funds are spent in order to develop the

skills needed. Nevertheless, the anticipation of

needs and the resources and career paths that

can become available can be difficult.

Government is taking steps aimed at making the

UK science base more responsive to the needs

of the economy. But while it is acknowledged

that the pull from industry should play an

important role in education and training, it

should be considered along with other important

variables when assessing strategic educational

requirements for the country.

5.9 Education and training model

The Bologna model provides a framework for

training systems biologists. If systems biology

training is based on the Bologna model, this

would comprise:

• BSc/BEng - three years, e.g. a first degree

in engineering or physics.

• MSc - two years, a masters in biology

or basic medical science.

• PhD - three years (minimum), a

doctorate in Systems Biology.

This model is not intended to be prescriptive

but provides a practical guide to systems

biology training. Whichever model is eventually

implemented, it must incorporate a significant

component of flexibility to accommodate

several special circumstances. For example,

issues may arise with regard to professional

78 www.hesa.ac.uk/holisdocs/pubinfo/stud.htm

79 Association of the British Pharmaceutical Industry, 2005

50


accreditation in subjects such as engineering,

where a four year MEng degree is required to

fulfil the academic requirements for chartered

status. This may be addressed by a specifically

designed five year funding scheme. Not all of

those submitting evidence agreed that the

proposed model was the best available and

some felt that it was too long. However,

MSc/PhD programmes can sometimes be

completed in five years, particularly if the MSc

component involves a project that can count

towards the first phase of the PhD. These

schemes can be very useful in that they allow

continuity of research during passage to

postgraduate level and consequently avoid

delays. The demands posed by systems biology

training should not be underestimated and to

compress the time required would inevitably

compromise the rigour and quality of the

training.

Medical degrees present another special case.

The training required to pursue a clinical

research career is extensive (11-12 years

minimum) and many feel that it is already

excessively long. In addition, most budding

clinical academics also undertake a three year

PhD in a laboratory discipline. Yet, for many of

the foreseen systems biology applications close

involvement of physicians is essential.

Experience shows that, despite initial fears of

mathematics, medical students can quickly

assimilate the subject to a surprisingly high

level of proficiency. Hence, one favoured

solution is to ensure the availability of courses

in engineering, mathematics and the physical

sciences during the first phases of medical

training. At the undergraduate level, optional

modules in mathematics, modelling and

simulation would help attract a more diverse

range of recruits, who would therefore provide

a more assorted set of skills and talents. At the

graduate level, one year intensive additional

courses should be made available to interested

medical graduates and supported by

appropriate training grants. The courses should

include a thorough module in mathematics,

followed by courses in systems theory, signal

processing, computer programming, modelling,

etc. Many medical schools are already

embracing interdisciplinary trends and

developing and implementing graduate entry

courses that provide an opportunity to attract

mathematically trained students into

biomedicine.

The Academies recommend that, given the

urgent need to develop the skills required

to undertake Systems Biology, new

postgraduate courses and the expansion of

postdoctoral opportunities should be

created. For instance, undergraduates,

including medical students, should be

offered options in the core disciplines that

support Systems Biology, as well as

increased exposure to interdisciplinary

problems and modules.

Further urgent action is needed to revive

subjects important to the development of

Systems Biology such as physiology,

pharmacology, engineering and

mathematics. Such initiatives in education

and training should be closely coordinated

with programmes in the BBSRC/EPSRC

centres.

Systems Biology is not simply an exercise

in mathematical modelling: it requires a

deep knowledge of the complexities of the

biomedical problem being addressed,

together with a thorough understanding of

the power and limitations of the

engineering and mathematical concepts

being used. Courses in biology and

medicine for engineers, mathematicians

and physical scientists are crucial, but they

must be combined with an expansion of

mathematical training for biological and

medical scientists to develop multi-skilled,

interdisciplinary teams. Initially, in view of

the shortage of trained personnel in the UK,

there may be a need to create schemes that

establish a new cadre of young systems

biologists, involving overseas recruitment

where necessary.

51

6 A TWENTY-FIVE YEAR VISION FOR SYSTEMS BIOLOGY

Presenting a realistic vision for Systems Biology

projecting more than two decades into the

future is difficult, not least because much of its

potential will depend on technological advances,

and it is hard to predict how far and how fast

these will occur. It is also a challenge to

formulate such a perspective without assuming

advances that, at the moment, may appear to

lie in the realms of science fiction. Nevertheless,

considering the advances that have

characterised the last 25 years, sceptics would

probably have made similar assertions in

relation to predicting our ability to achieve many

of the high-throughput, highly detailed

molecular technologies that are now almost

routine. At that time it was not anticipated that

the human genome would have been mapped

by 2005 and that stem cell and molecular

cloning technologies would have create cloned

animals. Neither was it envisaged quite how

great the impact of computers and network

technologies would have been in acquiring and

sharing data across the world. Coincidentally,

the personal computer, an invention that

unquestionably changed the world, has just

celebrated its 25th birthday. To quote the

American clergyman Harry Emerson Fosdick:

‘The world is moving so fast these days that

the one who says it can't be done is generally

interrupted by someone doing it’.

Perhaps one way to formulate a vision is by

considering how Systems Biology is expected

to develop by 2030, what tools it may produce,

the resources likely to be required to achieve

the objectives and, finally, by mapping out

milestones for the assessment of progress

towards these goals.

If the pace of technological development

proceeds as anticipated by the analysis

conducted in the 2029 Project, the impact of

Systems Biology on healthcare will be

substantial80. By that time, it is likely that

modelling of human disease will be the accepted

norm rather than the exception. This will lead to

a routine understanding of the physiological

mechanisms that are disrupted in the

pathogenesis of complex diseases and the

development of therapies whose effects are

understood in the context of the whole organism

rather than in isolated assays. Synthetic Biology

will have developed sufficiently for its areas of

application to have become clearly defined and

for business to invest confidently in the field.

Areas such as chemical engineering,

biomaterials, electronics and computing will be

undergoing significant transformation.

Multidisciplinary science will be routine, with

biologists, engineers and mathematicians all

able to communicate ‘in the same language’.

During this time, there will have been a clear

move from team working by scientists trained in

single disciplines to teams of scientists from

both biological and physical disciplines working

together on specific projects.

In order to address the challenges of human

health through the delivery of novel therapies,

academia and industry will have evolved

mechanisms of working together to develop

and apply new science more effectively. By this

time, it is likely that Systems Biology will have

become another tool to be applied

experimentally, much as molecular biology is

today, and will not demand the existence of

large, complex organisational infrastructures.

It is also probable that clinical support systems

that use systems biology equipment will have

become a routine part of improving care of

patients affected by multiple conditions who

require treatment with a wide array of possible

diagnostic and therapeutic alternatives.

80 Institute for Alternative Futures, 2005

6. A 25 year vision for Systems Biology

‘Prediction is difficult, especially if it concerns the future.’

Mark Twain, humorist and writer, 1835-1910

52


However, before this vision can become reality,

there is a need to build confidence in the ability

of Systems Biology to deliver tangible results

and value. In order to influence a change in

attitudes and working practices, and also to

break down conventional disciplinary barriers,

programmes of work will need to be designed

specifically to produce evidence aimed at

increasing confidence in, and understanding of,

the potential impact of Systems Biology.

The recommendations made in this report

represent suggestions that are essential steps

in this direction. The detailed programmes of

work that eventually underpin these

recommendations will need to be structured to

deliver tangible and measurable near, medium

and long-term objectives aimed ultimately at

achieving the 25 year vision. Central to the

success in achieving this is the urgent need to

establish effective and robust mechanisms for

industry and academia to cooperate in this task.

In a recent publication, the European Science

Foundation described Systems Biology as ‘a

Grand Challenge for Europe’, based on the

assertion that the initiative to establish and

realise the full potential of Systems Biology is

too great for any one nation to undertake

alone81. Delivering a concerted UK systems

biology initiative, as proposed in this report, will

offer a strong foundation to, and will also help

to steer, this emerging grand challenge towards

achieving the 25 year vision.

81 European Science Foundation, 2005

53

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56


Appendix I Working and review group members

Working group

Sir Colin Dollery FMedSci (Joint Chair)

The Academy of Medical Sciences and GlaxoSmithKline

Professor Richard Kitney OBE FREng (Joint Chair)

Imperial College London

Professor Richard Challis FREng

University of Nottingham

Professor David Delpy FRS FREng FMedSci

University College London

Professor David Edwards FMedSci


Dr Adriano Henney

AstraZeneca

Professor Tom Kirkwood FMedSci

Newcastle University

Professor Denis Noble CBE FRS FMedSci

University of Oxford

Professor Malcolm Rowland FMedSci

University of Manchester

Professor Lionel Tarassenko FREng


Professor David Williams FREng

University of Liverpool

Secretariat

Dr Loredana Santoro

Policy Advisor


Mr Laurie Smith

Senior Policy Officer

The Academy of Medical Sciences

57

APPENDIX I

Review group

Professor Lewis Wolpert CBE FRS FMedSci (Chair)

University College London

Sir Michael Brady FRS FREng


Professor Forbes Dewey

Massachusetts Institute of Technology

Professor Rodney Smallwood FREng

University of Sheffield

Professor Douglas Young FMedSci


Professor Hans Westerhoff

University of Manchester

58


Appendix II Acronyms and abbreviations

ATM Automated Teller Machine

BBSRC Biotechnology and Biological Sciences Research Council

BPS British Pharmacological Society

CISBs Centres for Integrative Systems Biology

CoMPLEX Centre for Mathematics and Physics in the Life Sciences and Experimental Biology

COX Cyclooxygenase

CSBC Cambridge Systems Biology Centre

CT Computerised Tomography

DNA Deoxyribonucleic Acid

DTC Doctoral Training Centre

DTI Department of Trade and Industry

EPSRC Engineering and Physical Sciences Research Council

EU European Unicn

FEBS Federation of the European Biochemical Societies

HEFCE Higher Education Funding Council for England

HER2 Human Epidermal Growth Factor Receptor 2

IP Intellectual Property

LDL Low-Density Lipoprotein

MIT Massachusetts Institute of Technology

MRC Medical Research Council

MRI Magnetic Resonance Imaging

mRNA Messenger Ribonucleic Acid

MRSA Methicillin-Resistant Staphylococcus aureus

NCISBM Nottingham Centre for Integrative and Systems Biology in Medicine

NERC Natural Environment Research Council

NHS National Health Service

NIH National Institute of Health

NSF National Science Foundation

RAE Research Assessment Exercise

R&D Research and Development

RTK Receptor Tyrosine Kinase

SHEFC Scottish Higher Education Funding Council

SMEs Small and Medium-Sized Enterprises

STEM Science, Technology, Engineering and Mathematics

UC University of California

UK United Kingdom

US United States of America

WTEC World Technology Evaluation Centre

59

APPENDIX III

Appendix III Consultation and call for evidence

Evidence was obtained using the following methods:

• Letters from the Chairmen of the working group were sent to the Vice-Chancellors of Russell

Group universities and Chief Executives of major UK biomedical and engineering research

funders requesting an overview of systems biology activity at their organisations. Russell

Group universities that declared substantive work in the field were then sent a second letter

containing a more detailed set of questions.

• Letters were sent to the Presidents of the medical Royal Colleges and selected Scientific

Societies to inquire about systems biology activity being undertaken by their organisations.

• Letters were sent to the Chief Executives of companies with known UK based R&D and possible

interest in Systems Biology inquiring about their activity in this area.

• Meetings were held between the Chairmen and representatives from the BBSRC, DTI, EPSRC,

MRC and Wellcome Trust.

• A wider call for evidence was placed on the websites of both Academies, which was also drawn

to the attention of individuals known to have an interest in the area.

Responses were received from the following organisations:

Government

• Department of Trade and Industry

• European Commission

• Office of Science and Innovation (formerly Office of Science and Technology)

• National Health Service R&D

Industry

• AstraZeneca

• GlaxoSmithKline

• Hewlett-Packard

• IBM

• Johnson & Johnson

• Novo Nordisk

• Pfizer

• Renovo

• Siemens

• Unilever

60


Medical Research Charities

• Arthritis Research Campaign

• Association of Medical Research Charities

• British Heart Foundation

• Cancer Research UK

• Wellcome Trust

Medical Royal Colleges

• Faculty of Dental Surgery

• Royal College of Anaesthetists

• Royal College of General Practitioners

• Royal College of Nursing

• Royal College of Obstetricians and Gynaecologists

• Royal College of Ophthalmologists

• Royal College of Paediatrics and Child Health

• Royal College of Pathologists

• Royal College of Physicians

• Royal College of Physicians of Edinburgh

• Royal College of Physicians and Surgeons of Glasgow

• Royal College of Surgeons

• Royal College of Surgeons of Edinburgh

Research and Funding Councils

• Biotechnology and Biological Sciences Research Council

• Economic and Social Research Council

• Engineering and Physical Sciences Research Council

• Higher Education Funding Council for England

• Higher Education Funding Council for Wales

• Medical Research Council

• Research Councils UK

• Scottish Higher Education Funding Council

Scientific Societies

• Association of Clinical Biochemists

• Biochemical Society

• British Computer Society

• British Nutrition Society

• British Pharmacological Society

• British Society for Cell Biology

• British Society for Proteome Research

• Institute of Biology

• Institute of Biomedical Sciences

• Institute of Physics

• Institute of Physics and Engineering in Medicine

• Institution of Chemical Engineers

• Institution of Engineering and Technology (formerly Institution of Electrical Engineers)

• London Mathematical Society

• Physiological Society

61

APPENDIX III

• Royal Pharmaceutical Society

• Royal Society

• Royal Society of Chemistry

• Royal Society of Edinburgh

• Royal Statistical Society

• Society for Experimental Biology

Universities

• Imperial College London

• King’s College London

• London School of Economics

• Newcastle University

• University College London

• University of Birmingham

• University of Bristol

• University of Cambridge

• University of Cardiff

• University of Edinburgh

• University of Glasgow

• University of Leeds

• University of Liverpool

• University of Manchester

• University of Nottingham

• University of Oxford

• University of Sheffield

• University of Southampton

• University of Surrey

• University of Warwick

Other

• GARnet

• Genome Arabidopsis Research Network

• Professor Erol Gelenbe

• Professor John Mathers

• Professor P M Williams

February 2007

Academy of Medical Sciences

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